Blood markers predictive of brain pathology and clinical outcome in parkinson's disease

Abstract

The present invention provides biological markers which are molecular markers and predictive of brain pathology and clinical status and / or outcome in Parkinson's disease (PD). The invention provides genes, RNA and protein markers that are associated with, relevant to, or predictive of Parkinson's disease (PD), Parkinson's disease with dementia (PDD), Parkinson's disease with dyskinesia or Parkinson's disease duration. The present invention further provides methods, kits and markers for the identification and monitoring of disease and disease aspects in Parkinson's patients and their application as markers and targets in and for evaluating, monitoring and treatment of Parkinson's disease and relevant pathologies and conditions associated with or developing in Parkinson's disease.

Description

BLOOD MARKERS PREDICTIVE OF BRAIN PATHOLOGY AND CLINICAL OUTCOME IN PARKINSON’S DISEASE CROSS REFERENCE TO RELATED APPLICATION

[0001] The present application claims priority to U.S. Application Serial No. 63 / 464,735, filed May 8, 2023, the entire contents of which is incorporated by reference herein. STATEMENT OF GOVERNMENT RIGHTS

[0002] This invention was made with government support under numbers NS081706 and R35NS097404 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD OF THE INVENTION

[0003] The present invention relates generally to the identification and characterization of biological markers which are molecular markers and predictive of brain pathology and clinical status and / or outcome in Parkinson’s disease (PD). The invention further relates to genes, RNA and protein markers that are associated with, relevant to, or predictive of Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), Parkinson’s disease with dyskinesia or Parkinson’s disease duration. The present invention relates to methods, kits and markers for the identification and monitoring of disease and disease aspects in Parkinson‘s patients and their application as markers and targets in and for evaluating, monitoring and treatment of Parkinson’s disease and relevant pathologies and conditions associated with or developing in Parkinson’s disease. BACKGROUND OF THE INVENTION

[0004] Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting 2-3% of the population over 65 years of age1–3. Clinically, PD is a highly heterogeneous disease with motor symptoms such as tremor, slowness of movements, stiffness, and postural instability, and more than half of PD patients develop PD dementia (PDD) within 10 years of diagnosis4–7. Patients with late onset of PD experience faster progression and are at increased risk of dementia while patients with early onset have slower progression, less frequent cognitive impairment, but more treatment related motor complications8. The disabling motor and non-motor manifestations of PD are primarily due to loss of dopaminergic input from the substantia nigra into the dorsal striatum1.

[0005] The main therapy for Parkinson’s disease is levodopa. Other medicines may also be prescribed and utilized to treat Parkinson’s symptoms, including Dopamine agonists to stimulate the production of dopamine in the brain, enzyme inhibitors (e.g., MAO-B inhibitors, COMT inhibitors) to increase the amount of dopamine by slowing down the enzymes that break down dopamine in the brain, amantadine to help reduce involuntary movements, or anticholinergic drugs to reduce tremors and muscle rigidity.

[0006] While the symptomatic therapeutic mainstay for PD remains levodopa, which restores brain dopamine levels, its chronic use is fraught with several problems, including loss of drug efficacy, erratic (on-off) responses, and abnormal hyperkinetic movements such as levodopa-induced dyskinesia, a common motor complication related to dopamine transporter loss and abnormal connectivity in the putamen17,18.

[0007] The molecular basis underlying the various clinical-pathologic features of PD remains incompletely understood and any assessment of molecular changes following dopamine denervation in the striatum has been surprisingly limited. Moreover, RNA changes have not been studied with respect to the heterogeneous clinical features of PD.

[0008] There remains a need for improved disease understanding, and disease and symptom and clinical features management in Parkinson’s disease patients, including those with Parkinson’s disease dementia (PDD) and those with dyskinesia. The present invention addresses such unmet needs with regard to Parkinson’s disease, including Parkinson’s disease with dementia (PDD) and PD with dyskinesia. Molecular changes in PD brain, including caudate and putamen, and in blood that underlie clinical heterogeneity in PD, have been evaluated and identified, providing RNA markers of potential pathophysiologic, diagnostic and prognostic importance.

[0009] The citation of references herein shall not be construed as an admission that such is prior art to the present invention. SUMMARY OF THE INVENTION

[0010] In a general aspect, the present invention provides markers, genes, RNAs associated with Parkinson’s disease (PD) or clinical aspects and conditions associated with Parkinson’s disease. RNA markers and protein markers have been identified which are differentially expressed or preferentially expressed in PD patient(s), and also in PD patients with certain associated conditions or pathologies, including Parkinson’s diesaes with dementia (PDD) and Parkinson’s disease with dyskinesia. These RNAs and their genes and associated proteins provide markers which can predict or monitor or evaluate Parkinson’s disease (PD) or aspects of Parkinson’s disease such as associated dementia or dyskinesia.

[0011] Various gene and RNA markers are provided herein that are associated with Parkinsons disease (PD), including with particular aspects of the disease, such as PD with dementia (PDD) or PDwith dyskinesia. These markers provide genes that are altered, up regulated or down regulated, and whose relevant RNA(s) are increased or decreased in Parkinson’s disease (PD), including in certain aspects of Parkinson’s disease (PD) such as and including in Parkinson’s disease with dementia (PDD) or PD with dyskinesia.

[0012] In some embodiments, markers, genes and their RNAs are provided in listings and tables herein. Markers and genes or RNAs associated with Parkinson’s disease (PD), including wherein the relevant or corresponding RNA is increased / upregulated or is decreased / downregulated in patients or individuals, particularly humans, with PD versus control individuals and patients or individuals without PD. These genes, RNAs or markers are associated with Parkinson’s disease (PD). Markers, genes, RNAs include those expressed in the brain and associated with PD and also those expressed in blood, particularly those expressed in blood and correlated with expression in brain, partciularly in caudate and / or in putamen. In some embodiments, the association with PD is irrespectve or and independent of the patients treatment, drugs being taken, or drug interventions.

[0013] Markers, genes, RNAs expressed in the the brain, particularly caudate and putamen, and associated with PD are provided in Table 4. The markers, genes, corresponding RNAs set out in Table 4 are increased or decreased in brain, including putamen and / or caudate, of patients with PD. Markers, genes, RNAs that are decreased or down regulated in the blood of patients with PD are set out in Table 13. Markers, genes, RNAs that are increased or upregulated in the blood of patients with PD are set out in Table 14. Methods and assays for evaluating PD in patients or individuals wherein one or more markers set out in Table 13 or set out in Table 14, or set out in Tables 13 and / or 14 are evaluated or assessed, including determining the relative expression or amount thereof, are provided herein and in embodiments hereof. Markers, genes, RNAs that are decreased or down regulated in the blood of patients with PD are set out in Table 6C. Markers, genes, RNAs that are increased or upregulated in the blood of patients with PD are set out in Table 6D. Methods and assays for evaluating PD in patients or individuals wherein one or more markers set out in Table 6C or set out in Table 6D, or set out in Tables 6C and / or 6D are evaluated or assessed, including determining the relative expression or amount thereof, are provided herein and in embodiments hereof. Classifier genes in caudate associated with PD are provided in Table 5A. Methods and assays for evaluating PD in patients or individuals wherein one or more markers associated with one or more the classifier genes set out in Table 5A are evaluated or assessed, including determining the relative expression or amount thereof, are provided herein and in embodiments hereof. Altered expression can be determined by comparison to one or more control or against a standard of expression, such as of or from unaffected individuals. In partiular embodiments, these methods include evaluating the expression or amount of one or more gene or RNA as set out in Table 13, in Table 14, or in Table 13 and 14. Markers, genes, RNAs increased in expression or amount in the blood and also the brain, caudate, of patients or individuals with PD are set out in Table 23. Markers, genes, RNAs decreased in expression or amount in the blood and also the brain, caudate, of patients or individuals with PDare set out in Table 24. Markers, genes, RNAs increased in expression or amount in the blood and also the brain, putamen, of patients or individuals with PD are set out in Table 25. Markers, genes, RNAs decreased in expression or amount in the blood and also the brain, caudate, of patients or individuals with PD are set out in Table 26. The markers provided in Tables 23-26 are increased or decreased in PD in patient blood, correlating with patient brain expression. The markers provided in Tables 23 and 25 are increased in PD in patient blood, correlating with patient brain expression. The markers provided in Tables 24 and 26 are decreased in PD in patient blood, correlating with patient brain expression. Methods and assays for evaluating PD disease in patients or individuals wherein one or more markers set out in Table 23, Table 24, Table 25 and / or Table 26 or set out in Tables 23-26 are provided herein and in embodiments hereof.

[0014] In some embodiments, the methods or assays hereof evaluate the genes, markers, RNA in blood, such as a blood sample, including blood samples collected and assessed over time or in regular intervals of time to assess expression or change in expression.

[0015] In an embodiment, genes and their RNAs are provided as down regulated in PD blood, even in drug naïve patients, versus control patients and are selected from one or more of GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4. In a particular embodiment, genes and their RNAs are provided as being down regulated in the blood of PD drug naive patients, in particular one or more of DNAJC6, SNCA, DLG2 and GPR52. In a further embodiment, genes TOMM70 and CAMK4 are down regulated in caudate and putamen of PD patients. TIAM1 is decreased or down regulated in blood, caudate and putamen in PD versus controls.

[0016] In another embodiment, genes and their RNAs are provided as being up regulated in PD blood, even in drug naïve patients, versus control patients and are selected from one or more of FCAR, PROK2, IL1R2, HSPA6 and CHRNA10. In a particular embodiment, one or more of genes FCAR, PROK2 and IL1R2 are up regulated in the blood of PD drug naive patients. In a particular embodiment, genes FCAR, PROK2 and IL1R2 are up regulated in the blood of PD drug naive patients.

[0017] In one embodiment, genes or their RNAs, selected from the following are up or down regulated and their expression or activity is altered in PD patients, even in drug naïve patients: GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL, CAMK4, FCAR, PROK2, IL1R2, HSPA6 and CHRNA10. Thus, in some embodiments, a kit or collection of markers corresponding to one or more of the following genes or their RNAs is provided in a kit or system for assessing and determining whether a patient has or is likely to have or become afflicted with Parkinson’s disease, even prior to any drug intervention: GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL, CAMK4, FCAR, PROK2, IL1R2, HSPA6 and CHRNA10. In a particular aspect, the kit or collection of markers is designed to evaluate the expression or activity of a gene, its RNA, or encoded protein in the blood of a patient or individual.

[0018] In an embodiment, a kit or collection of markers corresponding to one or more of the following genes or their RNAs is provided in a kit or system for assessing and determining whether a patient has or is likely to have or become afflicted with Parkinson’s disease, even prior to any drug intervention, whereby a decrease in expression or amount of one or more gene or corresponding RNA, or protein, in a sample from a patient or individual selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL, and CAMK4. In a particular aspect, the kit or collection of markers is designed to evaluate the expression or activity of a gene, its RNA, or encoded protein in the blood of a patient or individual.

[0019] In an embodiment, a kit or collection of markers corresponding to one or more of the following genes or their RNAs is provided in a kit or system for assessing and determining whether a patient has or is likely to have or become afflicted with Parkinson’s disease, even prior to any drug intervention, whereby an increase in expression or amount of one or more gene or corresponding RNA, or protein, in a sample from a patient or individual selected from FCAR, PROK2, IL1R2, HSPA6 and CHRNA10. In a particular aspect, the kit or collection of markers is designed to evaluate the expression or activity of a gene, its RNA, or encoded protein in the blood of a patient or individual.

[0020] The invention provides a method for assessing or evaluating Parkinson’s disease (PD) in a patient or individual comprising: (a) isolating a sample from said patient; (b) evaluating the sample for expression or quantitatively increased or decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 4; (ii) markers as provided in Table 13 or 14; (iii) markers as provided in Table 23, 24, 25 or 26; (iv) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4; (v) markers selected from FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (vi) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL, CAMK4, FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (vii) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4; and (viii) markers selected from FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (c) wherein the expression or quantitatively increased or decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) in a patient or individual.

[0021] The invention provides a method for assessing or evaluating Parkinson’s disease (PD) in a patient or individual comprising:(a) isolating a sample from said patient; (b) evaluating the sample for expression or quantitatively increased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 14; (ii) markers as provided in Table 23 or 25; and (iii) markers selected from FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (c) wherein the expression or quantitatively increased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) in a patient or individual.

[0022] The invention provides a method for assessing or evaluating Parkinson’s disease (PD) in a patient or individual comprising: (a) isolating a sample from said patient; (b) evaluating the sample for expression or quantitatively decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 13; (ii) markers as provided in Table 24 or 26; (iii) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4; and (iv) markers selected from GPR52, SNCA, DNAJC6 and DLG2; (v) markers selected from FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (c) wherein the expression or quantitatively decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) in a patient or individual.

[0023] The invention provides a method for assessing or evaluating Parkinson’s disease (PD) in a patient or individual comprising: (a) isolating a blood sample from said patient; (b) evaluating the blood sample for expression or quantitatively increased or decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (ii) markers as provided in Table 13 or 14; (iii) markers as provided in Table 23, 24, 25 or 26; (iv) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4; (v) markers selected from FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; and (vi) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL, CAMK4, FCAR, PROK2, IL1R2, HSPA6 and CHRNA10;(c) wherein the expression or quantitatively increased or decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) in a patient or individual.

[0024] The invention provides a method for assessing or evaluating Parkinson’s disease (PD) in a patient or individual comprising: (a) isolating a blood sample from said patient; (b) evaluating the blood sample for expression or quantitatively increased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 14; (ii) markers as provided in Table 23 or 25; and (iii) markers selected from FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (c) wherein the expression or quantitatively increased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) in a patient or individual.

[0025] The invention provides a method for assessing or evaluating Parkinson’s disease (PD) in a patient or individual comprising: (a) isolating a blood sample from said patient; (b) evaluating the blood sample for expression or quantitatively decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 13; (ii) markers as provided in Table 24 or 26; (iii) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4; and (iv) markers selected from GPR52, SNCA, DNAJC6 and DLG2; (c) wherein the expression or quantitatively decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) in a patient or individual.

[0026] Parkinson’s Disease with Dementia (PDD)

[0027] Markers and genes or RNAs associated with Parkinson’s disease with dementia (PDD), including wherein the relevant or corresponding RNA is increased / upregulated or is decreased / downregulated in patients or individuals, particularly humans, with Parkinson’s disease with dementia (PDD) versus patients or individuals with PD without dementia. These genes, RNAs or markers are associated with PD with dementia (PDD). Markers, genes, RNAs include those expressed in the brain and associated with PDD and also those expressed in blood, particularly those expressed in blood and correlated with expression in brain, partciularly in caudate and / or in putamen. In some embodiments, the association with PDD is irrespectve or and independent of the patients treatment, drugs being taken, or drug interventions.

[0028] Markers, genes, RNAs expressed in the brain, particularly caudate and / or putamen, and associated with PD with dementia (PDD) are provided in Tables 15, 16, 17, 18, 19, 27 and 28. GO terms associated with PDD and identified in patient blood are provifded in Table 9C. Markers, genes, RNAs expressed in the blood and associated with PDD are provided in Table 9B. Tables 8A and 8B provide a subset of particular markers, genes RNAs associated with PDD in the caudate and putamen respectively. The markers, genes, corresponding RNAs set out in Tables 8A and 8B are increased or decreased in brain, including putamen and / or caudate, of patients with PD with dementia (PDD). The markers, genes, corresponding RNAs set out in Tables 15, 16, 17, 18, 19, 27 and 28 are increased or decreased in brain, including putamen and / or caudate, of patients with PD with dementia (PDD). Markers, genes, RNAs that are decreased or down regulated in the caudate of patients with PDD are set out in Table 15. Markers, genes, RNAs that are increased or upregulated in the caudate of patients with PDD are set out in Table 16. Markers, genes, RNAs that are decreased or down regulated in the putamen of patients with PDD are set out in Table 17. Markers, genes, RNAs that are increased or upregulated in the putamen of patients with PDD are set out in Table 18. Markers, genes, RNAs that are increased / upregulated or are decreased / downregulated in the caudate of patients with PDD are set out in Table 19. Markers, genes, RNAs that are increased / upregulated or are decreased / downregulated in the caudate and also in the blood of patients with PDD are set out in Table 27 and Table 28. Methods and assays for evaluating PDD in patients or individuals wherein one or more markers set out in Tables 15, 16, 17, 18, 19, 27 and / or 28 are evaluated or assessed, including determining the relative expression or amount thereof, are provided herein and in embodiments hereof. Altered expression can be determined by comparison to one or more control or against a standard of expression, such as of or from unaffected individuals. In partiular embodiments, these methods include evaluating the expression or amount of one or more gene or RNA as set out in Tables 15, 16, 17, 18, 19, 27 and / or 28. Markers, genes, RNAs increased or decreased in expression or amount in the blood and also the brain, caudate, of patients or individuals with PDD are set out in Table 27 and Table 28. The markers provided in Tables 27 and / or 28 are increased or decreased in PDD in patient blood, correlating with patient brain expression. Methods and assays for evaluating PDD disease in patients or individuals wherein one or more markers set out in Tables 15, 16, 17, 18, 19, 27 and / or 28 are provided herein and in embodiments hereof. Methods and assays for evaluating PDD disease in patients or individuals wherein one or more markers set out in Tables 27 and / or 28 are evaluated in the blood or in a blood sample are provided herein and in embodiments hereof. In some embodiments, the methods or assays hereof evaluate the genes, markers, RNA in blood, such as a blood sample, including blood samples collected and assessed over time or in regular intervals of time to assess expression or change in expression.

[0029] In one embodiment, genes or their RNAs as provided in TABLE 8A or TABLE 8B are associated with PDD in the brain. In an embodiment, one or more genes or RNAs selected from TABLE 8A are altyered in caudate with PDD. In an embodiment, one or more genes or RNAsselected from TABLE 8B are altyered in putamen with PDD. In an embodiment, one or more genes or RNAs selected from RGPD5, TMEM150C, GPAT2, BTN2A2, PDE1A, SYTL2, BMP6 AND PELO are altered in brain, particularly putamen, with PDD.

[0030] The disclosure provides genes, or their associated RNA(s) which have been identified as being down regulated or up regulated in Parkinson’s disease with dementia (PDD) versus in PD without dementia. In one embodiment, genes or their RNAs selected from one or more of TRAPPC6A, NUCKS1, STAG3 and ARFRP1 are down regulated, or their RNA expression or amount are decreased, in caudate in Parkinson’s disease with dementia (PDD) versus in PD without dementia. In a particular embodiment, the genes TRAPPC6A and ARFRP1, or their respective RNA(s) are down regulated, decreased, or reduced in amount in blood in PDD patients versus PD without dementia. Thus, in one embodiment, TRAPPC6A and ARFRP1 provide blood markers indicative or predictive for PD with dementia in Parkinson’s patients, even in drug naïve blood. These genes provide a blood marker gene set for PDD.

[0031] In another embodiment, genes or their RNAs selected from one or more of MARS1, NFAT5, LONRF3, PPP1R15B and TARS1 are up regulated, or their RNA expression or amount are increased, in caudate in Parkinson’s disease with dementia (PDD) versus in PD without dementia.

[0032] In another embodiment, genes or their RNA(s) selected from one or more of NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115 are down regulated, or their RNA expression or amount is decreased, in putamen in Parkinson’s disease with dementia (PDD) versus in PD without dementia.

[0033] In another embodiment, genes or their RNA(s) selected from one or more of STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR are up regulated, or their RNA expression or amount is increased, in putamen in Parkinson’s disease with dementia (PDD) versus in PD without dementia.

[0034] In one embodiment, genes or their RNAs, selected from the following are up or down regulated and their expression or activity is altered in PD patients with dementia (PDD) versus PD patients without dementia: TRAPPC6A, NUCKS1, STAG3, ARFRP1, NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2, TMEM115, MARS1, NFAT5, LONRF3, PPP1R15B, TARS1 STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR.

[0035] Thus, in some embodiments, a kit or collection of markers corresponding to one or more of the following genes or their RNAs or their encoded proteins is provided in a kit or system for assessing and determining whether a patient has or is likely to have or become afflicted with Parkinson’s disease with dementia, in some embodiments even prior to any evident or consistent dementia symptoms or characteristics: TRAPPC6A, NUCKS1, STAG3, ARFRP1, NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2, TMEM115, MARS1, NFAT5, LONRF3, PPP1R15B, TARS1, STX17AS1, DACT1, DNAH8 and C1QTNF3- AMACR. The kit, collection or set of markers, such as or including but not limited to, gene or RNA probes or primers, or antibodies directed against the encoded protein(s) of the genes or markers orRNAs, may be directed against or include means to evaluate a subset of the genes, such as at least two or more genes, at least 2 genes, at least 3 genes, 3 or more genes, at least four genes, at least 5 genes, at least 5 or more genes, at least 6 genes, at least 7 genes, at least 8 genes, 10 genes, at least 10 genes, 10 or more genes, at least 12 genes, 12 or more genes, at least 15 genes, 15 or more genes, at least 18 genes, 18 or more genes, at least 20 genes, 20 or more genes, at least half of the genes, at least 75% of the genes, at least 80% of the genes, or all of the genes. In embodiments the kit, collection or set of markers is directed against 2 or more genes or RNAs or proteins, 3 or more genes or RNAs or proteins, 5 or more genes or RNAs or proteins, 7 or more genes or RNAs or proteins, 9 or more genes or RNAs or proteins, 10 or more genes or RNAs or proteins. In embodiments the kit, collection or set of markers is directed against at least 2, 3, 4, or 5 genes or RNAs or proteins.

[0036] In an embodiment, a kit or collection of markers corresponding to the genes TRAPPC6A and ARFRP1 or their RNAs is provided in a kit or system for assessing and determining whether a patient has or is likely to have or become afflicted with Parkinson’s disease with dementia (PDD), in some embodiments even prior to any drug intervention or dementia relevant indicators or symptoms, whereby an decrease in expression or amount of TRAPPC6A and ARFRP1 or their RNAs or encoded proteins in a sample from a patient or individual indicates that the patient or individual has or may likely or will develop dementia with Parkinson’s disease. In a particular aspect, the kit or collection of markers is designed to evaluate the expression or activity of a gene TRAPPC6A and / or ARFRP1, its RNA, or encoded protein in the blood of a patient or individual.

[0037] In another embodiment, genes or their RNAs, selected from the following are down regulated and their expression or activity is decreased in PD patients with dementia (PDD) versus PD patients without dementia: TRAPPC6A, NUCKS1, STAG3, ARFRP1 NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115. Thus, in an embodiment, a kit or collection of markers corresponding to one or more of the following genes or their RNAs is provided in a kit or system for assessing and determining whether one or more genes, or their relevant RNA(s) are decreased in a PD patient or patient suspected of PD, so as to determine whether a patient has or is likely to have or become afflicted with Parkinson’s disease with dementia: TRAPPC6A, NUCKS1, STAG3, ARFRP1 NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115.

[0038] In another embodiment, genes or their RNAs, selected from the following are up regulated and their expression or activity is increased in PD patients with dementia (PDD) versus PD patients without dementia: MARS1, NFAT5, LONRF3, PPP1R15B, TARS1 STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR. Thus, in an embodiment, a kit or collection of markers corresponding to one or more of the following genes or their RNAs is provided in a kit or system for assessing and determining whether one or more genes, or their relevant RNA(s) are increased in a PD patient or patient suspected of PD, so as to determine whether a patient has or is likely to have or becomeafflicted with Parkinson’s disease with dementia: MARS1, NFAT5, LONRF3, PPP1R15B, TARS1 STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR.

[0039] The invention provides a method for assessing or evaluating Parkinson’s disease with dementia (PDD) in a patient or individual comprising: (a) isolating a sample from said patient; (b) evaluating the sample for expression or quantitatively increased or decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 15, 16, 17, 18, 19, 27 or 28; (ii) markers as provided in Table 27 or 28; (iv) markers selected from TRAPPC6A, NUCKS1, STAG3 and ARFRP1; (v) markers selected from MARS1, NFAT5, LONRF3, PPP1R15B and TARS1; (vi) markers selected from NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115; (vii) markers selected from STX17AS1, DACT1, DNAH8 and C1QTNF3- AMACR; (vii) markers selected from TRAPPC6A, NUCKS1, STAG3, ARFRP1, NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2, TMEM115, MARS1, NFAT5, LONRF3, PPP1R15B, TARS1, STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR; (viii) markers selected from TRAPPC6A, NUCKS1, STAG3, ARFRP1, NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115; (vii) markers selected from MARS1, NFAT5, LONRF3, PPP1R15B, TARS1 STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR; and (c) wherein the expression or quantitatively increased or decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease with dementia (PDD) in a patient or individual.

[0040] The invention provides a method for assessing or evaluating Parkinson’s disease with dementia (PDD) in a patient or individual comprising: (a) isolating a sample from said patient; (b) evaluating the sample for expression or quantitatively increased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 16 or 18; (ii) markers selected from MARS1, NFAT5, LONRF3, PPP1R15B and TARS1; (iii) markers selected from STX17AS1, DACT1, DNAH8 and C1QTNF3- AMACR;(iv) markers selected from MARS1, NFAT5, LONRF3, PPP1R15B, TARS1 STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR; and (c) wherein the expression or quantitatively increased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease with dementia (PDD) in a patient or individual.

[0041] The invention provides a method for assessing or evaluating Parkinson’s disease with dementia (PDD) in a patient or individual comprising: (a) isolating a sample from said patient; (b) evaluating the sample for expression or quantitatively decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 15 or 17; (ii) markers selected from TRAPPC6A, NUCKS1, STAG3 and ARFRP1; (ii) markers selected from NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115; and (iv) markers selected from TRAPPC6A, NUCKS1, STAG3, ARFRP1, NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115; (c) wherein the expression or quantitatively decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease with dementia (PDD) in a patient or individual.

[0042] The invention provides a method for assessing or evaluating Parkinson’s disease with dementia (PDD) in a patient or individual comprising: (a) isolating a blood sample from said patient; (b) evaluating the blood sample for expression or quantitatively increased or decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 27 or 28; (c) wherein the expression or quantitatively increased or decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease with dementia (PDD) in a patient or individual.

[0043] Parkinson’s disease with Dyskinesia

[0044] In an additional embodiment, genes or markers are provided which are altered in Parkinson’s petients with dyskinesia. In an embodiment, genes or their RNA(s) are up regulated or their RNA expression or amount is increased, or are downregulated or their RNA expression or amount is decreased or reduced in Parkinson’s disease with dyskinesia.

[0045] Markers and genes or RNAs associated with Parkinson’s disease (PD), including wherein the relevant or corresponding RNA is increased / upregulated or is decreased / downregulated in patients or individuals, particularly humans, with PD with dyskinesia versus control individuals and / or patientsor individuals with PD without dyskinesia. These genes, RNAs or markers are associated with PD with dyskinesia. Markers, genes, RNAs include those expressed in the brain and associated with PD with dyskinesia and also those expressed in blood, particularly those expressed in blood and correlated with expression in brain, partciularly in caudate and / or in putamen. In some embodiments, the association with PD with dyskinesia is irrespectve or and independent of the patients treatment, drugs being taken, or drug interventions.

[0046] GO terms associated with dyskinesia and altered in putamen in PD patients with dyskinesia are provided in Table 10D. Genes or RNAs associated with one or more of the GO terms set out in Table 10D are suitable in methods hereof for evaluating or assessing or monitoring dyskinesia in PD patients. Particular markers, genes, RNAs expressed in the the brain, particularly caudate, and associated with PD with dyskinesia are provided in Table 10C. In a partiuclar embodiment, particular markers, genes, RNAs expressed in the the brain, particularly putamen, and associated with PD with dyskinesia are provided in Table 10B. Methods and assays for evaluating PD with dyskinesia in patients or individuals wherein one or more markers set out in Table 10B or described in TABLE 10C are evaluated or assessed, including determining the relative expression or amount thereof, are provided herein and in embodiments hereof. In an embodiment, one or more marker is selected from NGF, EXOC3L1, CCDC172, ITGB3, STX17-AS1, VWA2, DACT1, CPTP, LINC01574, C1QTNF3- AM, MIER2, C9orf129, SLCO4A1-AS1, EFCC1, TMEM115, C1orf1116, DNAH8 and CAGE1.

[0047] Markers, genes, RNAs expressed in the the brain, particularly putamen, and associated with PD with dyskinesia are provided in Table 20. The markers, genes, corresponding RNAs set out in Table 20 are increased or decreased in brain, including putamen, of patients with PD with dyskinesia. Markers, genes, RNAs that are are increased or decreased in brain, including putamen, and in the blood of patients with PD with dyskinesia are set out in Table 29 and 30. Markers, genes, RNAs that are increased / upregulated or are decreased / downregulated in the blood of patients with PD with dyskinesia are set out in Table 29 and 20. In an embodiment, one or more marker is selected from FTCDNL1, MAF1, THEM4, TSTA3, XKRX, KANSL1-AS1, NUDT15, LINC00269, TMEM80, TMPO-AS1, ALAS2, TUBB4B, AHSP, EIF3C, WDR45, KIFC3 and CDC34. Methods and assays for evaluating PD with dyskinesia in patients or individuals wherein one or more markers set out in Table 29 or described in TABLE 30 are evaluated or assessed, including determining the relative expression or amount thereof, are provided herein and in embodiments hereof. Altered expression can be determined by comparison to one or more control or against a standard of expression, such as of or from unaffected individuals. In partiular embodiments, these methods include evaluating the expression or amount of one or more gene or RNA as set out in Tables 20 and / or 29 or in Table 30. In partiular embodiments, these methods include evaluating the expression or amount of one or more gene or RNA selected from FTCDNL1, MAF1, THEM4, TSTA3, XKRX, KANSL1-AS1, NUDT15, LINC00269, TMEM80, TMPO-AS1, ALAS2, TUBB4B, AHSP, EIF3C, WDR45, KIFC3 and CDC34. Methods and assays for evaluating PDD disease in patients or individuals wherein one ormore markers set out in Tables 29 or 30 are evaluated in the blood or in a blood sample are provided herein and in embodiments hereof. Methods and assays for evaluating PDD disease in patients or individuals wherein one or more markers selected from FTCDNL1, MAF1, THEM4, TSTA3, XKRX, KANSL1-AS1, NUDT15, LINC00269, TMEM80, TMPO-AS1, ALAS2, TUBB4B, AHSP, EIF3C, WDR45, KIFC3 and CDC34 are evaluated in the blood or in a blood sample are provided herein and in embodiments hereof. In some embodiments, the methods or assays hereof evaluate the genes, markers, RNA in blood, such as a blood sample, including blood samples collected and assessed over time or in regular intervals of time to assess expression or change in expression.

[0048] In an embodiment, genes or RNAs, or encoded proteins, selected from the genes provided in Table 20, 29 and / or 30 are altered in dyskinesia with Parkinson’s disease. In an embodiment, genes or RNAs, or encoded proteins, selected from the genes provided in Table 29 and / or 30 are altered in dyskinesia with parkinson’s disease.

[0049] In an embodiment, genes or their RNA(s) selected from one or more of selected from FTCDNL1, MAF1, THEM4, TSTA3, XKRX, KANSL1-AS1, NUDT15, LINC00269, TMEM80, TMPO-AS1, ALAS2, TUBB4B, AHSP, EIF3C, WDR45, KIFC3 and CDC34 are differentially expressed such that they are up regulated or down regulated, or their RNA expression or amount is increased or decreased, in Parkinson’s disease with dyskinesia versus in PD without associated dyskinesia. In an embodiment, these genes or RNAs are altered in brain, including putamen, and in blood. In an embodiment, these genes or RNAs are altered in blood. In an embodiment, changes in one or nmore of these genes or their RNAs expression can be identified by analysis of a patient’s blood, particularly a Parkinson’s disease patient or patient suspected of having Parkinson’s disease, particularly a patients peripheral blood.

[0050] The invention provides a method for assessing or evaluating Parkinson’s disease (PD) with dyskinesia in a patient or individual comprising: (a) isolating a sample from said patient; (b) evaluating the sample for expression or quantitatively increased or decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 20; (ii) markers as provided in Table 29 and / or 30; and (iv) markers selected from FTCDNL1, MAF1, THEM4, TSTA3, XKRX, KANSL1-AS1, NUDT15, LINC00269, TMEM80, TMPO-AS1, ALAS2, TUBB4B, AHSP, EIF3C, WDR45, KIFC3 and CDC34; (c) wherein the expression or quantitatively increased or decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) with dyskinesia in a patient or individual.

[0051] The invention provides a method for assessing or evaluating Parkinson’s disease (PD) with dyskinesia in a patient or individual comprising:(a) isolating a blood sample from said patient; (b) evaluating the blood sample for expression or quantitatively increased or decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 29 and / or 30; and (ii) markers selected from FTCDNL1, MAF1, THEM4, TSTA3, XKRX, KANSL1-AS1, NUDT15, LINC00269, TMEM80, TMPO-AS1, ALAS2, TUBB4B, AHSP, EIF3C, WDR45, KIFC3 and CDC34; (c) wherein the expression or quantitatively increased or decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) with dyskinesia in a patient or individual.

[0052] The invention provides a method for assessing or evaluating Parkinson’s disease (PD) with dyskinesia in a patient or individual comprising: (a) isolating a blood sample from said patient; (b) evaluating the blood sample for expression or quantitatively increased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from FTCDNL1, THEM4, KANSL1-AS1, LINC00269, TMPO-AS1 and EIF3C; (c) wherein the expression or quantitatively increased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) with dyskinesia in a patient or individual.

[0053] The invention provides a method for assessing or evaluating Parkinson’s disease (PD) with dyskinesia in a patient or individual comprising: (a) isolating a blood sample from said patient; (b) evaluating the blood sample for expression or quantitatively decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from MAF1, TSTA3, TUBB4B, WDR45, KIFC3 and CDC34; (c) wherein the expression or quantitatively decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) with dyskinesia in a patient or individual.

[0054] Markers and genes or RNAs associated with Parkinson’s disease (PD), including wherein the relevant or corresponding RNA is increased / upregulated or is decreased / downregulated in patients or individuals, particularly humans, with PD with disease duration versus control individuals and / or patients or individuals with PD without disease duration or earlier in the disease. These genes, RNAs or markers are associated with PD with disease duration. Markers, genes, RNAs include those expressed in the brain, particularly in putamen or caudate, and associated with PD with disease duration. Correlative markers expressed in the blood of patients or individuals are contemplated in one embodiment. In some embodiments, the association with PD with disease duration is irrespectve or and independent of the patients treatment, drugs being taken, or drug interventions.

[0055] Markers, genes, RNAs expressed in the caudate and associated with PD with disease duration are provided in Table 12B. Markers, genes, RNAs expressed in the putamen and associated with PD with disease duration are provided in Table 12C. The markers provided in Table 12B and 12C are increased or decreased in PD with disease duration. Methods and assays for evaluating PD disease duration in patients or individuals wherein one or more markers set out in Table 12B or set out in Table 12C, or set out in Tables 12B and / or 12C are provided herein and in embodiments hereof.

[0056] Markers, genes, RNAs expressed in the caudate and associated with PD with disease duration are provided in Table 21. Markers, genes, RNAs expressed in the putamen and associated with PD with disease duration are provided in Table 22. The markers provided in Table 21 and 22 are increased or decreased in PD with disease duration. Methods and assays for evaluating PD disease duration in patients or individuals wherein one or more markers set out in Table 21 or set out in Table 22, or set out in Tables 21 and / or 22 are provided herein and in embodiments hereof.

[0057] The invention provides a method for assessing or evaluating Parkinson’s disease (PD) with disease duration in a patient or individual comprising: (a) isolating a sample from said patient; (b) evaluating the sample for expression or quantitatively increased or decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 21 and / or 22; (c) wherein the expression or quantitatively increased or decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) with disease duration in a patient or individual.

[0058] In an embodiment of the methods, a subset of at least 20 of the markers are evaluated. In an embodiment, all of the markers in a Table are evaluated, such as all of the markers in Table 13, 14, 15, 16, 17, 18, 29 or 30. In an embodiment, a subset of at least 10 of the markers are evaluated. At least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50 of the markers in a Table or a listing of markers are or may be evaluated.

[0059] Evaluation of RNA or protein expression assessed using any method known in the art. Evaluation of RNA expression can be conducted by quantitative RNA analysis. Thus, in accordance with the methods of the invention, RNA expression or amount may be assessed by RT PCR. In accordance with the method, protein expression may be assessed using specific antibodies.

[0060] Marker expression, particularly protein expression as encoded by the genes or RNAs provided herein, including marker expression or presence on the surface of cells in the blood or in the cells in the blood in accordance with the methods of the invention may be determined using standard and known methods. Cell markers may be evaluated using antibodies. Cell markers may be evaluatedusing Fluorescent Activated Cell Sorting (FACs) analysis. Cells or cell markers may be evaluated using cell sorting or single cell assessments.

[0061] In embodiments of the methods, methods are provided for assessment or evaluation of one or more markers to determine PD disease or PD associated clinical aspects in a patient, wherein the patient is then treated with or administered one or more agent or therapy based on the assessment and evaluation. In one embodiment, a patient wherein PD is determined or predicted based on markers and RNA or gene expression or associated protein markers, the patient is then administered an agent or drug for treatment or alleviation of PD. In one embodiment, a patient wherein PDD is determined or predicted based on markers and RNA or gene expression or associated protein markers, the patient is then administered an agent or drug for treatment or alleviation of dementia. In one embodiment, a patient wherein PD associated dyskinesia is determined or predicted based on markers and RNA or gene expression or associated protein markers, the patient is then administered an agent or drug for treatment or alleviation of dyskinesia. In embodiments of the method of the invention, the agent or therapy for treating PD may be selected from standard or clinically recognized agents or therapies for PD. In embodiments of the method of the invention, the agent for treating PD may be one or more agent selected from levodopa, dopamine agonists, and MAO-B inhibitors. In an embodiment of the method of the invention, the agent for treating PD may be one or more agent selected from the PD agents and therapies described and provided herein. In embodiments of the method of the invention, the agent or therapy for treating PDD may be selected from standard or clinically recognized agents or therapies for dementia, PDD, or Alzheimer‘s. In embodiments of the method of the invention, the agent for treating PDD may be one or more agent selected from cholinetsrease inhibitors and dementia medications used to treat Alzheimer’s disease. Anticholinergics include Trihexyphenidate, Trihexyphenidyl. Drugs or agents to treat or alleviate dementia symptoms include Donepezil, Memantine, Rivastigmine and Ginkgo Biloba. In embodiments of the method of the invention, the agent or therapy for treating PD dyskinesia may be selected from standard or clinically recognized agents or therapies for dyskinesia. In embodiments of the method of the invention, the agent for treating PD may be one or more agent selected from dopamine agonists or dopamine promoters include bromocriptine, pergolide, pramipexole (or Mirapex), amantadine, ropinirole, piribedil, cabergoline, apomorphine, Requip XL, and lisuride as well as the Rotigotine transdermal system. In an embodiment of the method of the invention, the agent for treating PD dyskinesia may be one or more agent selected from the dyskinesia agents and therapies or the agents which control, alter or manage dopamine levels described and provided herein.

[0062] Other objects and advantages will become apparent to those skilled in the art from a review of the ensuing detailed description, which proceeds with reference to the following illustrative drawings, and the attendant claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] The patent or patent application contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the U.S. Patent and Trademark Office upon request and payment of the necessary fee.

[0064] Figure 1A-1G Transcriptome differences in PD caudate and putamen. (A) Overview of the study. RNA-sequencing and mass spectrometry was performed in postmortem caudate and putamen from controls and PD patients. Antemortem blood transcriptome data was obtained from an independent cohort of subjects enrolled in the PPMI study. Clinical information was extracted from accompanying charts (postmortem donors) and open-access database (PPMI subjects) to determine molecular profiles associated with PD clinical variables. (B) Principal component analysis (PCA) shows separation of caudate and putamen regions of striatum along PC1 (p value: 2.6*10-20, Kruskal- Wallis test). Healthy controls and PD are separated along PC2 (p value: 2.08*10-8). Ellipses indicate confidence interval = 0.8 of indicated groups. (C) Volcano plot shows significantly changed RNAs in PD caudate and putamen compared to their respective controls. RNAs with changes in expression (determined by limma) with false discovery rate (FDR) < 0.05 and absolute value of log2 fold change (FC, PD / Control) > 0.1, 0.5 and 1 are colored according to direction. (D) Bubble plot shows representative top significantly (FDR < 0.05) up- (log2FC > 0) and down (log2FC < 0) -regulated GO terms in both caudate and putamen, as determined by GSVA. (E) Sample-wise gene set enrichment scores (determined by GSVA) for individual donors show select GO terms that are changed in both regions. (F) Gene set enrichment scores for individual donors show select GO terms that are preferentially changed in either caudate or putamen. (G) Heatmap shows expression (log2(counts per million), scaled by genes) of classifier genes (identified in caudate) in control and PD striatum. Significance for box-plots were determined by the Wilcoxon test. ** p value < 0.01, **** p value < 0.0001, ns: not significant.

[0065] Figure 2A-2F Transcriptome changes in PD striatum (A) Tyrosine hydroxylase (TH) protein levels in PD caudate (n=5) and putamen (n=5) are significantly lower compared to controls (n=5). TH levels were estimated by ELISA in 120 micrograms of total protein from respective regions. p values were obtained from unpaired two-tailed Student’s t-test ** p < 0.01 (B) Principal component 2 scores of RNA-seq (from Figure 1b) correlate with TH levels in PD caudate (n=35). Linear regression lines are shown in blue, with 95% confidence intervals shaded in gray. (C) Scatter plot of changes in enrichment scores (log2FC) for GO terms that are preferentially enriched (determined by GSVA) in PD caudate and putamen compared to respective controls are highlighted. GO terms were highlighted as preferentially enriched in caudate if FDR < 0.05 in caudate and FDR > 0.1 in putamen. Likewise, preferentially enriched GO terms in putamen had FDR < 0.05 in putamen and FDR > 0.1 in caudate. Gray dots indicate all GO terms in analysis. (D) Gene ontology analysis of highly changed RNAs (FDR < 0.05, absolute value of log2 FC > 1) in PD caudate and putamen compared to respective controls. (E) Venn diagrams show overlap of differentially expressed RNAs in PD and RNAs changed independent of dopaminergic medication dose in PD. Only RNAs withabsolute log2FC > 0.1 and FDR < 0.05 are shown (F) Correlation plot of differentially changed pathways (log2FC, calculated by GSVA) in PD compared to controls and pathways changed in PD independent of medication dose. Correlation coefficient (r) and p values were determined by Pearson’s correlation test.

[0066] Figure 3A-3D Mass spectrometry in PD striatum (A) Correlation plot for mean RNA expression (RNA-seq) and protein expression (mass spectrometry) in control (RNA-seq, n=40; Mass spectrometry, n=5) and PD caudate (RNA-seq, n=35; Mass spectrometry, n=10). (B) Gene set enrichment analysis shows top differentially changed pathways on mass spectrometry in PD caudate (C) Correlation plot for mean RNA and protein expression in control (RNA-seq, n=40; Mass spectrometry, n=6) and PD (RNA-seq, n=35; Mass spectrometry, n=12) putamen. (D) GSEA for top differentially changed pathways on mass spectrometry in putamen. For correlation plots, values were obtained from Pearson’s correlation test.

[0067] Figure 4A-4E. Concordant RNA changes are seen in PD brain and blood (A) Volcano plot showing differential gene expression analysis of blood transcriptome from PPMI subjects. Select RNAs that are also significantly up- or downregulated in the PD striatum (caudate or putamen) are labeled. Controls (n=195), PD (n=479). Only significantly (FDR < 0.05) changed (log2FC > 0.1 or < - 0.1) RNAs in PD blood are colored according to direction. (B) Cumulative distribution function plots show that top (FDR < 0.05, log2FC > 0.5 or log2FC < -0.5) changed RNAs in the PD caudate and putamen (n=35 each) are collectively differentially expressed in the same direction in blood from controls (n=195) and PD (n=479) subjects in the PPMI cohort. p-values were calculated using Kolmogorov-Smirnov tests. (C) RNA expression box plot showing log2(cpm) for select RNAs significantly changed in the striatum (controls (n=40), PD (n=35)) and blood (PPMI) in controls (n=195) and PD (n=479) subjects. p values were determined by the Wilcoxon tests. C: Control (D) Volcano Plot shows significantly (FDR < 0.05) changed GO terms in PD blood compared to controls. Select top GO terms are labeled. (E) Gene set enrichment scores of the top downregulated GO term (extrinsic component of postsynaptic density membrane) in PD blood correlate with disease progression, based on Hoehn and Yahr scale and MDS-UPDRS III motor scores. p values were obtained from the Wilcoxon test. Only significant comparisons as determined by Wilcoxon tests are shown. * p < 0.05, ** p < 0.01, **** p < 0.0001

[0068] Figure 5A-5E Concordance between blood and brain RNA changes in PD. (A) Venn diagram showing overlap of RNAs that are significantly (FDR < 0.05) up- (log2FC > 0.1) and down- (log2FC < -0.1) -regulated in the caudate and putamen and blood from controls (n=195) and PD (n = 479) subjects in the PPMI cohort. (B) CDF plot of changes in GO term enrichment scores (log2FC / SE) shows that GO terms that are significantly (FDR < 0.05) up- (log2FC > 0) and down- (log2FC < 0) -regulated in the PD brain as identified by GSVA are collectively up and downregulated in the blood, respectively. p values were calculated using Kolmogorov-Smirnov tests. (C) Volcano plots show that direction of change in top differentially changed GO terms in PD blood are driven bychanges in most RNAs in the GO term. All RNAs are plotted in black, and RNAs within the indicated GO term are shown in blue. (D) Boxplots show that RNA expression levels (log2(cpm)) of TIAM-1, one of the RNAs in the GO term extrinsic component of postsynaptic density membrane, is downregulated in the blood of PPMI PD subjects and correlates with motor progression as shown by MDS-UPDRSIII scores. TIAM-1 is also downregulated in postmortem PD caudate and putamen. Significance was determined by Wilcoxon tests. ** p value < 0.01, *** p value < 0.001 (E) CDF plots show that differentially changed RNAs in PD striatum (caudate) show concordant changes in the blood of prodromal subjects (n=60)27but not in genetic carriers (n=247) who are otherwise healthy. p values were obtained from Kolmogorov-Smirnov tests.

[0069] Figure 6A-6I PD RNA changes seen in blood is independent of medication effect. (A) Venn diagrams show overlap of differentially expressed RNAs in PD and RNAs changed independent of medication dose, among PPMI subjects on dopaminergic medications when compared to controls. (B) Cumulative distribution plot of gene expression changes in the blood (log2FC / SE) shows that differentially (FDR < 0.05, absolute value of log2FC > 0.1 or log2FC < -0.1) expressed RNAs in PD blood after accounting for medication dose (LEDD) show concordant changes with RNAs in the PD striatum. p values were obtained from Kolmogorov-Smirnov tests. (C) Changes in pathway enrichment (log2FC) are plotted both before and after accounting for medication dose. Blue line indicates y=x. (D) MDS-UPDRS total and motor (MDS-UPDRS III) scores are plotted in drug- naive and medicated PD patients in the PPMI cohort. Significance was obtained from Wilcoxon tests. (E) Overlap of drug-naive PD (n = 463) blood transcriptome with postmortem striatum RNA changes in the PD caudate and putamen. (F) Volcano plot shows significantly (FDR < 0.05) changed (absolute value of log2FC > 0.1) RNAs in drug-naive PD blood compared to controls. Select brain RNAs changed in the same direction are highlighted. (G) Expression plots for RNAs changed in PD striatum such as SNCA, the PD gene DNAJC6, GPR52 and FCAR show changes in blood in drug- naive PD subjects. Significance was obtained from Wilcoxon tests. (H) Correlation plot comparing changes between enrichment scores (log2FC) in the blood of PD subjects on dopaminergic medications and drug-naive subjects when compared to controls. (I) Classifier RNAs identified in drug-naive early PD45show similar changes in postmortem PD striatum. Significance was obtained from Kolmogorov-Smirnov tests. ** p < 0.01, **** p < 0.0001

[0070] Figure 7A-7D Caudate is affected in PDD with concordant changes seen in blood (A) Volcano plot shows differentially expressed RNAs in PDD caudate (n=16) compared to PD without dementia (PD) (n=11). Only significantly (FDR < 0.05) changed (absolute value of log2FC > 0.1) RNAs are colored according to direction. (B) Bubble plot shows representative top significant (FDR < 0.05) GO terms from GSVA analysis in PDD caudate compared to PD. (C) GSVA enrichment scores of select GO terms in controls, PD and PDD. Controls (n=40), PD (n=11), PDD (n=16) p values were determined by Wilcoxon tests. (D) Differentially changed RNAs in the PDD caudate show similar changes in expression levels in PD blood with worsening cognition as seen by Montreal CognitiveAssessment (MoCA) scores. Only significant comparisons as determined by Wilcoxon tests are shown. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, ns: not significant.

[0071] Figure 8A-8H Transcriptome patterns in PDD caudate are reflected in the blood of PD subjects with cognitive impairment, including those who were drug-naive. (A) Volcano plot shows few differentially expressed RNAs in PDD putamen (n=16) compared to PD without dementia (PD) (n=11). Significantly (FDR < .05) changed (absolute value of log2FC > 0.1) RNAs are colored according to direction. (B) GSVA identified significantly changed pathways in PDD caudate but not putamen. Pathways with FDR < 0.05 are colored according to direction. (C) Volcano plot shows differentially expressed RNAs in PD blood of subjects with abnormal cognition (MoCA < 26, n=144) compared to those with normal MoCA scores (n=332). Only significantly (FDR< 0.05) changed (absolute value of log2FC > 0.1) RNAs are colored according to direction. (D) Differential enrichment of GO terms based on GSVA in the blood of PPMI PD subjects with abnormal MoCA (n=144) compared to subjects with normal MoCA scores (n=332). Only differentially changed GO terms with FDR < 0.05 and log2FC > 0 and log2FC < 0 are colored according to direction. Select top GO terms are labeled. (E) Enrichment scores of top GO terms significantly changed in PDD caudate change with cognitive impairment (as determined by MoCA scores) in the blood of PPMI subjects. Only significant comparisons as determined by Wilcoxon tests are shown. (F) Among PPMI subjects with abnormal MoCA scores (n=144), those who were drug-naive (n=112) had significantly better cognitive performance than those on medications for dementia (n=32). (data not shown). Significance was determined by the Wilcoxon test. (G) Drug-naive PPMI patients were grouped according to MoCA scores (26-30, 22-25 and 0-21) and expression levels of RNAs significantly changed in the PDD caudate are plotted in the blood for these groups. (H) Enrichment scores of top pathways changed in PDD caudate were also changed in the drug-naive blood. Only significant comparisons as determined by Wilcoxon tests are shown. * p < 0.05, ** p < 0.01.

[0072] Figure 9A-9D Putamen is preferentially affected in PD dyskinesia. (A) Volcano plot shows differentially expressed RNAs in PD dyskinesia (n=5) putamen compared to PD without dyskinesia (n=11). Only RNAs with FDR < 0.1 and absolute value of log2FC >0.1 are colored according to direction. Similar analysis in the caudate show few differentially expressed RNAs between those with and without dyskinesia (B) Volcano plot shows differentially enriched GO terms in PD dyskinesia compared to PD without dyskinesia in the putamen than in the caudate. Only GO terms that are differentially (FDR < 0.25) changed are colored according to direction. (C) Bubble plot shows top differentially regulated GO terms from GSVA in the putamen in patients with and without dyskinesia. (D) Gene set enrichment scores of top differentially affected GO term plotted in controls and PD patients without and with dyskinesia shows downregulation of the gene set in PD dyskinesia putamen. p-values are the result of Wilcoxon test * p value < 0.05

[0073] Figure 10A-10D PD caudate and putamen from patients with later onset PD (LOPD) show significant changes in RNA levels compared to controls. (A) PC2 values (from Figure 1b)distinguish LOPD (n=25), but not EOPD (n=6) samples from controls (n=40) in both the caudate and putamen. For each region, controls are plotted individually with EOPD (left) and LOPD (right) samples and colored accordingly. p values for separation of the groups along PC2 were obtained from Kruskal-Wallis test. p = 0.05 (Caudate, EOPD and Control), p = 0.0006 (Caudate, LOPD and Control), p = 0.07 (Putamen, EOPD and Control) p = 0.0007 (Putamen, LOPD and Control). Ellipses indicate confidence interval = 0.8 of indicated groups. (B) Volcano plots show differential gene expression for LOPD and EOPD compared to controls in caudate (left) and putamen (right). Only significantly changed RNAs (FDR < 0.05, absolute value of log2FC > 0.1) are colored according to direction. (C) Gene set enrichment scores for GO terms are plotted for LOPD, EOPD and controls (C) in the caudate and putamen. Changes detected in PD donors with LOPD when compared to controls are not significant in those with EOPD compared to controls. p-values are the result of the Wilcoxon test (D) Volcano plots show differential gene expression analysis in LOPD and EOPD compared to controls in the blood. Only RNAs with FDR < 0.05 and absolute value of log2FC > 0.1 are colored according to direction. Control (n=195); LOPD, PD onset >55 (n=330); EOPD, PD onset <= 55 (n=149). * p < 0.05, ** p < 0.01, **** p < 0.0001 ns: not significant

[0074] Figure 11A-11D LOPD and EOPD striatum are molecularly distinct with comparable loss of dopamine input (A) Differential gene expression analysis was performed on 50 randomly chosen groups (n=6) of LOPD compared to all controls (n=40). Median numbers of significantly (FDR < 0.05 and absolute log2FC > 0.1) changed RNAs in these analyses are shown, grouped according to the direction of change. CAU: Caudate, PUT: Putamen (B) Differential gene expression analysis was performed on 50 different groups of equal number (n=6) of randomly chosen controls and LOPD, and all 6 EOPD donors. Median numbers of significantly changed RNAs from analyses are shown. (C) Enzyme-linked immunosorbent assay shows comparable levels of Tyrosine hydroxylase (TH), a marker for dopamine innervation into the striatum in EOPD (n=6) and LOPD (n=25) donors in the caudate. Significance was determined by unpaired two-tailed t-tests. (D) Western blot for TH in putamen shows decreased dopamine innervation in both LOPD and EOPD compared to controls (C) Quantification of relative intensity of TH is normalized to GAPDH in LOPD and EOPD compared to controls. n=3 per group. Significance was determined by unpaired two-tailed Student’s t- test ** p < 0.01, ns: not significant

[0075] Figure 12A-12D Disease duration correlates with distinct molecular changes in caudate and putamen. (A,B) Heatmaps show significant (FDR < 0.05) GO terms associated with disease duration in PD caudate (A) and putamen (B), identified by spline regression analysis. Scaled expression (log2(cpm)) values are plotted. (C, D) Scatter plots show GSVA enrichment scores for top significant GO terms plotted against disease duration in caudate (C) and putamen (D). Blue lines indicate loess regression lines, with 95% confidence intervals shaded in gray. DETAILED DESCRIPTION

[0076] In accordance with the present invention there may be employed conventional molecular biology, microbiology, and recombinant DNA techniques within the skill of the art. Such techniques are explained fully in the literature. See, e.g., Sambrook et al, "Molecular Cloning: A Laboratory Manual" (1989); "Current Protocols in Molecular Biology" Volumes I-III [Ausubel, R. M., ed. (1994)]; "Cell Biology: A Laboratory Handbook" Volumes I-III [J. E. Celis, ed. (1994))]; "Current Protocols in Immunology" Volumes I-III [Coligan, J. E., ed. (1994)]; "Oligonucleotide Synthesis" (M.J. Gait ed. 1984); "Nucleic Acid Hybridization" [B.D. Hames & S.J. Higgins eds. (1985)]; "Transcription And Translation" [B.D. Hames & S.J. Higgins, eds. (1984)]; "Animal Cell Culture" [R.I. Freshney, ed. (1986)]; "Immobilized Cells And Enzymes" [IRL Press, (1986)]; B. Perbal, "A Practical Guide To Molecular Cloning" (1984).

[0077] Therefore, if appearing herein, the following terms shall have the definitions set out below. A. TERMINOLOGY

[0078] The term “antibody” describes an immunoglobulin whether natural or partly or wholly synthetically produced. The term also covers any polypeptide or protein having a binding domain which is, or is homologous to, an antibody binding domain. CDR grafted antibodies are also contemplated by this term. An "antibody" is any immunoglobulin, including antibodies and fragments thereof, that binds a specific epitope. The term encompasses polyclonal, monoclonal, and chimeric antibodies. The term “antibody(ies)” includes a wild type immunoglobulin (Ig) molecule, generally comprising four full length polypeptide chains, two heavy (H) chains and two light (L) chains, or an equivalent Ig homologue thereof (e.g., a camelid nanobody, which comprises only a heavy chain); including full length functional mutants, variants, or derivatives thereof, which retain the essential epitope binding features of an Ig molecule, and including dual specific, bispecific, multispecific, and dual variable domain antibodies; Immunoglobulin molecules can be of any class (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), or subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2). Also included within the meaning of the term “antibody” are any “antibody fragment”.

[0079] An “antibody fragment” means a molecule comprising at least one polypeptide chain that is not full length, including (i) a Fab fragment, which is a monovalent fragment consisting of the variable light (VL), variable heavy (VH), constant light (CL) and constant heavy 1 (CH1) domains; (ii) a F(ab')2 fragment, which is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a heavy chain portion of an Fab (Fd) fragment, which consists of the VH and CH1 domains; (iv) a variable fragment (Fv), which consists of the VL and VH domains of a single arm of an antibody, (v) a domain antibody (dAb) fragment, which comprises a single variable domain (Ward, E.S. et al., Nature 341, 544-546 (1989)); (vi) a camelid antibody; (vii) an isolated complementarity determining region (CDR); (viii) a Single Chain Fv Fragment wherein a VH domain and a VL domain are linked by a peptide linker which allows the two domains to associate to form an antigen binding site (Bird et al, Science, 242, 423-426, 1988; Huston et al, PNAS USA, 85, 5879-5883, 1988); (ix) a diabody, which is a bivalent, bispecific antibody in which VH andVL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with the complementarity domains of another chain and creating two antigen binding sites (WO94 / 13804; P. Holliger et al Proc. Natl. Acad. Sci. USA 90 6444-6448, (1993)); and (x) a linear antibody, which comprises a pair of tandem Fv segments (VH-CH1-VH-CH1) which, together with complementarity light chain polypeptides, form a pair of antigen binding regions; (xi) multivalent antibody fragments (scFv dimers, trimers and / or tetramers (Power and Hudson, J Immunol. Methods 242: 193-204 9 (2000)); (xii) a minibody, which is a bivalent molecule comprised of scFv fused to constant immunoglobulin domains, CH3 or CH4, wherein the constant CH3 or CH4 domains serve as dimerization domains (Olafsen T et al (2004) Prot Eng Des Sel 17(4):315-323; Hollinger P and Hudson PJ (2005) Nature Biotech 23(9):1126-1136); and (xiii) other non-full length portions of heavy and / or light chains, or mutants, variants, or derivatives thereof, alone or in any combination.

[0080] As antibodies can be modified in a number of ways, the term "antibody" should be construed as covering any specific binding member or substance having a binding domain with the required specificity. Thus, this term covers antibody fragments, derivatives, functional equivalents and homologues of antibodies, including any polypeptide comprising an immunoglobulin binding domain, whether natural or wholly or partially synthetic. Chimeric molecules comprising an immunoglobulin binding domain, or equivalent, fused to another polypeptide are therefore included.

[0081] The term “adjuvant(s)” describes a substance, compound, agent or material useful for improving an immune response or immune cell or component stimulation, and may in some instances be combined with any particular antigen in an immunological, pharmaceutical or vaccine composition. Adjuvants can be used to increase the amount of antibody and effector T cells produced and to reduce the quantity of antigen or immune stimulant or modulator and the frequency of injection. An adjuvant can serve as a tissue depot that slowly releases the antigen and also as a lymphoid system activator that non-specifically enhances the immune response. In a preferred aspect an adjuvant is physiologically and / or pharmaceutically acceptable in a mammal, particularly a human.

[0082] The term “specific” may be used to refer to the situation in which one member of a specific binding pair will not show any significant binding to molecules other than its specific binding partner(s). The term is also applicable where e.g. an antigen binding domain is specific for a particular epitope which is carried by a number of antigens, in which case the specific binding member carrying the antigen binding domain will be able to bind to the various antigens carrying the epitope.

[0083] The term “comprise” generally used in the sense of include, that is to say permitting the presence of one or more features or components. The term “consisting essentially of” refers to a product, such as a peptide sequence, of a defined number of residues which is not covalently attached to a larger product.

[0084] The term "oligonucleotide," as used herein in referring to a probe of use the present invention, is defined as a molecule comprised of two or more ribonucleotides, preferably more than three. Its exact size will depend upon many factors which, in turn, depend upon the ultimate function and use of the oligonucleotide. The term "primer" as used herein refers to an oligonucleotide, which is capable of acting as a point of initiation of synthesis when placed under conditions in which synthesis of a primer extension product, which is complementary to a nucleic acid strand, is induced, i.e., in the presence of nucleotides and an inducing agent such as a DNA polymerase and at a suitable temperature and pH. The primer may be either single-stranded or double-stranded and must be sufficiently long to prime the synthesis of the desired extension product in the presence of the inducing agent. The exact length of the primer will depend upon many factors, including temperature, source of primer and use of the method. For example, for diagnostic applications, depending on the complexity of the target sequence, the oligonucleotide primer typically contains 15-25 or more nucleotides, although it may contain fewer nucleotides.

[0085] The term "agent" means any molecule, including polypeptides, antibodies, polynucleotides, chemical compounds and small molecules. In particular the term agent includes compounds such as test compounds or drug candidate compounds.

[0086] The term "assay" means any process used to measure a specific property of a compound. A "screening assay" means a process used to characterize or select compounds based upon their activity from a collection of compounds.

[0087] The term "protein" is used herein to mean protein, polypeptide, oligopeptide or peptide. The terms "protein marker", "biomarker" are used herein to refer to proteins associated with or predictive or which precede specific diseases or conditions or symptoms, including proteins from or associated with aspects, cells or tissues affected by a disease or condition or symptom.

[0088] As used herein, the terms "increase" in marker, gene, RNA expression or "differential expression“ of a marker refer to a statistically significant increase or presence. The term statistically significant is used in the art to refer to the likelihood that a result or relationship is caused by something other than mere random chance. Statistical hypothesis testing is traditionally employed to determine if a result is statistically significant or not. Such testing provides a "p-value" representing the probability that random chance could explain the result. In general, a 5% or lower p-value is considered to be statistically significant.

[0089] As used herein, the terms "decrease" in marker, gene, RNA expression or "differential expression“ of a marker refer to a statistically significant decrease, reduced presence or absense. The term statistically significant is used in the art to refer to the likelihood that a result or relationship is caused by something other than mere random chance. Statistical hypothesis testing is traditionally employed to determine if a result is statistically significant or not. Such testing provides a "p-value" representing the probability that random chance could explain the result. In general, a 5% or lower p- value is considered to be statistically significant.

[0090] A skilled practitioner would, moreover, appreciate that a relative increase or decrease in a particular protein (a protein marker) or a particular RNA (an RNA marker) or gene expression in a sample alone may be weakly indicative or predictive of disease, but may not be diagnostic per se, if noted as a single determinant. If, however, a plurality of such single determinants are noted in a biological sample, the combined detection of several, even weakly indicative, determinants may serve to identify a strong combinatorial diagnostic indicator of impending disease or symtpomatic disease aspects, such as PD or a clinical aspect of PD including dementia, dyskinesia. Furthermore, the single protein / determinant need not approach the threshold of weak diagnostic by itself but in combination with the detection of an increase of another protein or proteins or RNA or RNAs (other markers) or gene expression may serve as a strong combinatorial diagnostic indication of a disease state or disease aspect or an impending disease state or disease aspect. Accordingly, also encompassed herein are combinatorial diagnostic indicators or combinatorial markers that are associated with a particular disease or disease aspect / characteristic or an impending disease or disease aspect / characteristic and not observed in healthy subjects or patients with other diseases.

[0091] Accordingly, selected sets of one, two, three, several, at least 10, about 10, a dozen, 10-15, about 20, at least 20, 25, 30, about 30 and more, etc of the markers of this invention (up to the number equivalent to all of the markers, or all in a set of markers, including any intervening number, in whole number increments, e.g., 1, 2, 3, 4, 5, 6 ... ) can be used as diagnostic indicators and predictors of a particular disease or disease aspect / characteristic for methods and / or in kits described herein. In one embodiment, larger numbers of the markers identified herein are used in methods or kits of the invention, since the accuracy of the method or kit may improve as the number of markers screened increases. With respect to aspects of the invention pertaining to evaluating therapeutic efficacy, the methods and kits of the present invention include evaluating whether administration of a therapeutic composition causes a change, either a transient change or a long term change, in expression of one or more of the markers; in expression of two or more of the markers; in expression of three or more of the biomarkers; in expression of four or more of the biomarkers; in expression of five or more of the biomarkers, in expression of six or more of the biomarkers, etc.

[0092] As an example, a straightforward identification of a protein marker or an RNA marker or gene is the presence or increased amount of a protein or RNA associated with a disease or condition and not with other conditions or a decreased amount or the absence of a protein or RNA associated with a disease or condition and not with other conditions that might be clinically confused with the disease under consideration. Variations to this scenario include the situation wherein a marker is present in an increased quantity compared to other conditions or controls. Variations to this scenario include the situation wherein a marker is present in an decreased quantity compared to other conditions or controls. Although not a protein marker, an example is the presence of glucose in the blood in high quantities in diabetics compared to normal individuals who have glucose present but not in elevated quantities. A variation is where the functional marker is not just one protein, RNA or genebut two or more in combination that can be quantitatively different, wherein the ensemble defines its marker potential.

[0093] In some embodiments, a marker of the invention is a member of a biological pathway. As used herein, the term "precursor" or "successor" refers to molecules that precede or follow the marker in the biological pathway. Thus, once a marker is identified as a member of one or more biological pathways, the present invention can include additional members of the biological pathway that come before (are upstream of or a precursor of) or follow (are downstream of) the marker. Such identification of biological pathways and their members is within the skill of one in the art.

[0094] Also encompassed herein is the analysis of markers identified and listed in the tables presented herein to identify metabolic pathways implicated in the pathogenesis, maintenance, and / or progression of a disease or an impending disease or disease aspect or characteristic, such as dyskinesia or dementia. Such analyses may utilize a variety of software programs or approaches known and available to the skilled artisan. Multiple hits in a particular metabolic pathway underscore the potential importance of the pathway for the disease and direct therapeutic intervention toward appropriate modulation of same. Accordingly, the present methods encompass such analyses and the identification of metabolic pathways of potential significance in a particular disease or impending disease aspect or symptom. Knowing that, for example, activation of a metabolic pathway appears to be linked or associated with a particular disease or impending symptom presents the opportunity to test pharmaceutical modulators of the pathway (i.e., inhibitors) to determine if such modulators could be used as therapeutics for treatment of patients with the disease or impending disease or symptoms. This and these aspects are illustrated and described herein including in the examples.

[0095] Polypeptide or protein markers and RNA(s) or RNA markers may be isolated or evaluated by any suitable method known in the art. Proteins or RNAs can be purified or assayed by standard methods known in the art such as via immunoassay, ELISA, nucleic acid probes, primers, oligonicleotides, antibody affinity methods, RNA sequencing etc. In one embodiment, polypeptide and metabolite markers may be isolated from a biological sample using standard techniques known in the art, for example, affinity purification using substrate-bound antibodies that specifically bind to the marker. As described herein, immunoaffinity depletion of abundant RNA(s) or proteins (with masking potential) enhances coverage and detection of low abundance proteins or RNA(s).

[0096] Antibodies immunospecific for any one of the markers provided herein may be known and available to the public and may be accessed via the scientific community or purchased from a commercial vendor. Readily searchable databases or web browsers may be utilized for example for identifying potential suppliers for such antibodies.

[0097] In accordance with the present disclosure, the tables present information with which an ordinarily skilled practitioner can access the amino acid or nucleic acid sequences of the proteins, genes and RNAs identified herein as markers, as well as nucleic acid sequences encoding same. A stepwise protocol or means for identification of the sequences listed in the tables presented hereinmay include the artisan accessing one of the publicly available databases and entering the ensembl number or gene name or symbol to identify the sequence and relevant marker information. Such information may be used to design probes for detection of any of the proteins, genes, RNAs listed therein or to identify commercially available probes or antibodies therefore or thereof. Primers for detection of nucleic acid sequences encoding any of the proteins listed in the tables presented herein are also envisioned as are primers for PCR including RT PCR. Such primers may be used to detect RNA expression levels (including relative increases or decreases as compared to controls) of a marker relevant to the invention. The design of primers for detecting expression levels of RNA ( e.g., mRNA) of a marker or markers listed herein is a matter of routine practice with the nucleic acid sequence in hand as provided by publicly available websites such as those mentioned above. Such probes and primers are useful for the kits described herein.

[0098] The term "preventing" or "prevention" refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop) in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset. The term "prophylaxis" is related to and encompassed in the term ‘prevention’, and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines;the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.

[0099] "Therapeutically effective amount" means that amount of a drug, compound, antibody, or pharmaceutical agent that will elicit the biological or medical response of a subject that is being sought by a medical doctor or other clinician. In particular, with regard to gram-positive bacterial infections and growth of gram-positive bacteria, the term “effective amount” is intended to include an effective amount of a compound or agent that will bring about a biologically meaningful decrease in the amount of or extent of disease or symptom free or reduced time period and or increase in length of a subject’s survival or period disease-free or in remission or free of dyskinesia, dementia, or other PD associated symptoms.The phrase "therapeutically effective amount" is used herein to mean an amount sufficient to prevent, and preferably reduce by at least about 20 percent, preferably reduce by at least about 30 percent, more preferably by at least 50 percent, more preferably by at least 70 percent, most preferably by at least 90 percent, a clinically significant change, or enhanced survival or disease-free or clinical symptom or disease aspect free period by at least about 30 percent, more preferably by at least 50 percent, most preferably by at least 90 percent. [000100] The term "treating" or "treatment" of any disease, condition, or infection refers, in one embodiment, to ameliorating the disease or infection (i.e., arresting the disease or growth of the infectious agent or bacteria or reducing the manifestation, extent or severity of at least one of theclinical symptoms thereof). In another embodiment "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In another embodiment, "treating" or "treatment" refers to modulating the disease or infection, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In a further embodiment, "treating" or "treatment" relates to slowing the progression of a disease or reducing an infection. [000101] The phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human. [000102] As used herein, "pg" means picogram, "ng" means nanogram, "ug" or "µg" mean microgram, "mg" means milligram, "ul" or "µl" mean microliter, "ml" means milliliter, "l" means liter. B. DETAILED DISCLOSURE. [000103] The invention relates to and provides previously unidentified and unrecognized markers and marker sets, particularly gene, RNA markers and corresponding protein markers, which are indicators of and associated with Parkinson’s disease, or clinical aspects of Parkinson’s disease, particularly Parkinson’s disease with dementia (PDD) or dyskinesia Parkinson’s disease. The markers are differentially expressed or preferentially expressed in conjunction with Parkinson’s disease, or clinical aspects of Parkinson’s disease, particularly Parkinson’s disease with dementia (PDD) or dyskinesia Parkinson’s disease in a patient or indvidual and provide markers which can indicate Parkinson’s disease, or clinical aspects of Parkinson’s disease, particularly Parkinson’s disease with dementia (PDD) or dyskinesia Parkinson’s disease, and can be utilized to implement and prescribe treatment and therapy to a patient. [000104] The concordant transcriptome changes seen in brain and blood can be leveraged to molecularly characterize clinical subtypes of PD and develop novel tools for antemortem clinical diagnosis, prognostication and monitoring therapeutic responses by a minimally invasive approach. [000105] Parkinson’s disease is a central nervous system disorder that affects movement, causing unintended or uncontrollable movements, such as shaking, stiffness, and difficulty with balance and coordination. Parkinson’s is a neurodegenerative disorder that affects predominately the dopamine- producing (“dopaminergic”) neurons in the substantia nigra area of the brain. Nerve cell damage in the brain causes dopamine levels to drop, leading to the symptoms of Parkinson's. [000106] People with Parkinson’s disease also lose the nerve endings that produce norepinephrine, the main chemical messenger of the sympathetic nervous system, which controls many functions of the body, such as heart rate and blood pressure. The loss of norepinephrine may help explain some of the non-movement features of Parkinson’s, such as fatigue, irregular blood pressure, decreased movement of food through the digestive tract, and sudden drop in blood pressure when a person stands up from a sitting or lying position. Many brain cells of people with Parkinson’s disease contain Lewy bodies, unusual clumps of the protein alpha-synuclein.[000107] Symptoms and clinical aspects of Parkinson’s disease generally develop slowly over years. The progression of symptoms can be different from one person to another due to the diversity of the disease. People with PD may experience: tremor, mainly at rest and described as pill rolling tremor in hands, other forms of tremor are possible; slowness and paucity of movement (called bradykinesia and hypokinesia); limb stiffness (rigidity); gait and balance problems (postural instability). In addition to movement-related (“motor”) symptoms, Parkinson’s symptoms may be unrelated to movement (“non-motor”). People with PD can be more impacted by their non-motor symptoms than motor symptoms. Examples of non-motor symptoms include: depression, anxiety, apathy, hallucinations, constipation, orthostatic hypotension, sleep disorders, loss of sense of smell, and a variety of cognitive impairments. Cognitive impairments can progress to dementia. [000108] Dyskinesia [000109] Dyskinesia is and includes involuntary, erratic, writhing movements of the face, arms, legs or trunk. They are often fluid and dance-like, but they may also cause rapid jerking or slow and extended muscle spasms. They are not a symptom of Parkinson's disease (PD) alone but are associated with PD in some patients. Dyskinesia may occur with long-term levodopa use and longer time with Parkinson's. Dyskinesia can involve one body part, such as an arm or leg, or the entire body. It can look like fidgeting, writhing, wriggling, head bobbing or body swaying. [000110] Researchers believe a number of brain chemicals, including serotonin, glutamate and dopamine, play a role in dyskinesia. Dopamine is particularly important. In Parkinson's, the brain cells that make dopamine are lost, so dopamine levels decrease. Levodopa temporarily restores dopamine, but because some of the levodopa medication has to be taken several times per day, dopamine levels can rise and fall. These fluctuating levels, and the continued loss of dopamine-producing brain cells, make it impossible to keep a steady level of dopamine, which contributes to dyskinesia. [000111] Treatment options for dyskinesia include: changing the dose and / or timing of levodopa; switching to a different formulation of levodopa, such as extended-release (Rytary) or the gel infusion (Duopa), which aims to keep dopamine levels steady to control symptoms and limit dyskinesia; adding amantadine or Gocovri (amantadine extended release) works on the glutamate brain chemical system to lessen dyskinesia. Also, under-the-skin levodopa pumps are designed to keep dopamine levels consistent to control symptoms and prevent dykinesia. Other treatment approaches include deep brain stimulation (DBS) or focused ultrasound. The Michael J. Fox Foundation has created and validated a tool, the Unified Dyskinesia Rating Scale, to measure and assess dyskinesia, including measuring the impact of dyskinesia therapies in trials. [000112] Dementia and PDD [000113] Cognitive impairment is common in Parkinson's disease (PD) and involves attentional, executive, visuospatial, and memory dysfunctions. Dementia describes a set of symptoms that gradually get worse over time and affect daily life. Dementia symptoms occur when nerve cells in the brain become damaged and eventually die. The condition usually involves problems with memory,thinking, communication and mood. Symptoms and associated features include forgetfulness, slowed thinking and difficulty concentrating, increasing difficulty to make decisions, plan activities and solve problems, sleep disturbances, changes in appetite, and mental health problems such as anxiety, depression or agitation, hallucinations or delusions. Parkinson's dementia and dementia with Lewy bodies are the two types of dementia most likely to affect people with Parkinson's. If there have been motor symptoms (such as tremor or rigidity) for at least one year before dementia symptoms occur, specialists will often give a diagnosis of Parkinson's dementia. [000114] Disease Treatments [000115] The main families of drugs useful for treating motor symptoms of PD are levodopa, dopamine agonists, and MAO-B inhibitors. The treatment approach varies depending on the disease stage. Two phases are usually distinguished: an initial phase in which the individual with PD has already developed some disability which requires pharmacological treatment, and a second stage in which the patient develops motor complications related to levodopa usage. Treatment in the initial state aims to attain an optimal tradeoff between good management of symptoms and side effects resulting from enhancement of dopaminergic function. The start of L-DOPA treatment may be delayed by using other medications such as MAO-B inhibitors and dopamine agonists, in the hope of delaying the onset of dyskinesias. In the second stage, the aim is to reduce symptoms while controlling fluctuations of the response to medication. Sudden withdrawals from medication, and overuse by some patients, also must be controlled. When medications are not enough to control symptoms, surgical techniques such as deep brain stimulation (DBS) can relieve the associated movement disorders. [000116] The main therapy for Parkinson’s disease is levodopa. Other medicines may also be prescribed and utilized to treat Parkinson’s symptoms, including Dopamine agonists to stimulate the production of dopamine in the brain, enzyme inhibitors (e.g., MAO-B inhibitors, COMT inhibitors) to increase the amount of dopamine by slowing down the enzymes that break down dopamine in the brain, amantadine to help reduce involuntary movements, or anticholinergic drugs to reduce tremors and muscle rigidity. [000117] Levodopa is often taken along with another medication carbidopa, which prevents or reduces some of the side effects of levodopa therapy (nausea, vomiting, low blood pressure, and restlessness) and reduces the amount of levodopa needed to improve symptoms. Carbidopa and benserazide are peripheral dopa decarboxylase inhibitors. They inhibit the metabolism of L-DOPA in the periphery, thereby increasing levodopa delivery to the central nervous system and are generally given as combination preparations with levodopa. Available and utilized preparations include carbidopa / levodopa (co-careldopa, trade names Sinemet, Pharmacopa, Atamet) and benserazide / levodopa (co- beneldopa, trade name Madopar). Controlled, slow-release versions of Sinemet and Madopar spread out the effect of the levodopa. Duodopa is a combination of levodopa and carbidopa.[000118] Tolcapone inhibits the catechol-O-methyltransferase (COMT) enzyme, which degrades dopamine and levadopa, thereby prolonging the therapeutic effects of levodopa, and has been used alongside inhibitors of peripheral dopa decarboxylase to complement levodopa. A similar drug is entacapone, which is available for treatment alone (COMTan) or combined with carbidopa and levodopa (Stalevo). Stalevo is a commercial preparation of entacapone, levodopa, and carbidopa. [000119] Levodopa preparations lead to the development of motor complications characterized by involuntary movements called dyskinesias and fluctuations in the response to medication. When this occurs, PD patients change rapidly from stages with good response to medication and few symptoms ("on" state) to phases with no response to medication and important motor symptoms ("off" state). For this reason, levodopa doses are kept as low as possible while maintaining functionality. The on-off phenomenon is an almost invariable consequence of sustained levodopa treatment in patients with Parkinson's disease. Redistribution of levodopa dosage which may mean smaller, more frequent doses, or larger less frequent increments, may be helpful in controlling oscillations in some patients. Dietary protein restriction and the use of selegiline (Eldepryl) and bromocriptine may also temporarily improve motor fluctuations. New approaches to management include the use of subcutaneous apomorphine, controlled-release preparations of levodopa with a peripheral dopa decarboxylase inhibitor and the continuous intraduodenal administration of levodopa. [000120] Dopamine agonists in the brain have a similar effect to levodopa since they bind to dopaminergic postsynaptic receptors. Dopamine agonists were initially used for patients experiencing on-off fluctuations and dyskinesias as a complementary therapy to levodopa, but they are now mainly used on their own as an initial therapy for motor symptoms with the aim of delaying motor complications. When used in late PD, they are useful at reducing the off periods. Dopamine agonists or dopamine promoters include bromocriptine, pergolide, pramipexole (or Mirapex), amantadine, ropinirole, piribedil, cabergoline, apomorphine, Requip XL, and lisuride as well as the Rotigotine transdermal system. [000121] Apomorphine, which is a dopamine agonist not orally administered, may be used to reduce off periods and dyskinesia in late PD. Apomorphine can be administered by subcutaneous injection using a small pump which is carried by the patient. Nausea and vomiting are common, and may require domperidone (an antiemetic). [000122] Monoamine oxidase inhibitors (selegiline or Eldepryl and rasagiline) increase the level of dopamine in the basal ganglia by blocking its metabolization. Similarly to dopamine agonists, MAO- B inhibitors improve motor symptoms and delay the need of taking levodopa when used as monotherapy in the first stages of the disease, but produce more adverse effects and are less effective than levodopa. [000123] Some evidence indicates other drugs such as amantadine and anticholinergics may be useful as treatment of motor symptoms in early and late PD, but since the quality of evidence on efficacy is reduced, they are not first-choice treatments. Donepezil (Aricept), which boosts the level of theneurotransmitter acetylcholine, may help prevent falls in people with Parkinson's. Clozapine (Clozaril) is useful in the treatment of psychotic symptoms of PD. Cholinetsrease inhibitors and dementia medications used to treat Alzheimer’s disease may be utilized in treatment or amelioration of Parkinson’s disease dementia (PDD). Anticholinergics include Trihexyphenidate, Trihexyphenidyl. Drugs or agents to treat or alleviate dementia symptoms include Donepezil, Memantine, Rivastigmine and Ginkgo Biloba. [000124] Provided herein are methods for evaluating and assessing Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), Parkinson’s associate dyskinesia, and / or Parkinson’s with disease duration. [000125] Thus, a method is provided for assessing or evaluating Parkinson’s disease (PD) in a patient or individual comprising: (a) isolating a sample from said patient; (b) evaluating the sample for expression or quantitatively increased or decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 4; (ii) markers as provided in Table 13 or 14; (iii) markers as provided in Table 23, 24, 25 or 26; (iv) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4; (v) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL, CAMK4, FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; and (vi) markers selected from FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (c) wherein the expression or quantitatively increased or decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) in a patient or individual. [000126] A method is provided for assessing or evaluating Parkinson’s disease (PD) in a patient or individual comprising: (a) isolating a sample from said patient; (b) evaluating the sample for expression or quantitatively increased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 14; (ii) markers as provided in Table 23 or 25; and (iii) markers selected from FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (c) wherein the expression or quantitatively increased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) in a patient or individual.[000127] A method is provided for assessing or evaluating Parkinson’s disease (PD) in a patient or individual comprising: (a) isolating a sample from said patient; (b) evaluating the sample for expression or quantitatively decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 13; (ii) markers as provided in Table 24 or 26; (iii) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4; and (iv) markers selected from GPR52, SNCA, DNAJC6 and DLG2; (v) markers selected from FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (c) wherein the expression or quantitatively decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) in a patient or individual. [000128] Methods are provided wherein a blood sample is isolated and evaluated for expression or quantitatively increased or decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (ii) markers as provided in Table 13 or 14; (iii) markers as provided in Table 23, 24, 25 or 26; (iv) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4; (v) markers selected from FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; and (vi) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL, CAMK4, FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (c) wherein the expression or quantitatively increased or decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) in a patient or individual. [000129] Methods are provided wherein a blood sample is isolated and evaluated for expression or quantitatively increased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 14; (ii) markers as provided in Table 23 or 25; and (iii) markers selected from FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (c) wherein the expression or quantitatively increased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) in a patient or individual.[000130] Methods are provided wherein a blood sample is isolated and evaluated for expression or quantitatively decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 13; (ii) markers as provided in Table 24 or 26; (iii) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4; and (iv) markers selected from GPR52, SNCA, DNAJC6 and DLG2; (c) wherein the expression or quantitatively decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) in a patient or individual. [000131] Methods are provided for assessing or evaluating Parkinson’s disease with dementia (PDD) in a patient or individual comprising: (a) isolating a sample from said patient; (b) evaluating the sample for expression or quantitatively increased or decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 15, 16, 17, 18, 19, 27 or 28; (ii) markers as provided in Table 27 or 28; (iv) markers selected from TRAPPC6A, NUCKS1, STAG3 and ARFRP1; (v) markers selected from MARS1, NFAT5, LONRF3, PPP1R15B and TARS1; (vi) markers selected from NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115; (vii) markers selected from STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR; (viii) markers selected from TRAPPC6A, NUCKS1, STAG3, ARFRP1, NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2, TMEM115, MARS1, NFAT5, LONRF3, PPP1R15B, TARS1, STX17AS1, DACT1, DNAH8 and C1QTNF3- AMACR; (ix) markers selected from TRAPPC6A, NUCKS1, STAG3, ARFRP1, NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115; (x) markers selected from MARS1, NFAT5, LONRF3, PPP1R15B, TARS1 STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR; and (c) wherein the expression or quantitatively increased or decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease with dementia (PDD) in a patient or individual. [000132] A method is provided for assessing or evaluating Parkinson’s disease with dementia (PDD) in a patient or individual comprising: (a) isolating a sample from said patient;(b) evaluating the sample for expression or quantitatively increased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 16 or 18; (ii) markers selected from MARS1, NFAT5, LONRF3, PPP1R15B and TARS1; (iii) markers selected from STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR; (iv) markers selected from MARS1, NFAT5, LONRF3, PPP1R15B, TARS1 STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR; and (c) wherein the expression or quantitatively increased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease with dementia (PDD) in a patient or individual. [000133] Methods are provided for assessing or evaluating Parkinson’s disease with dementia (PDD) in a patient or individual comprising: (a) isolating a sample from said patient; (b) evaluating the sample for expression or quantitatively decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 15 or 17; (ii) markers selected from TRAPPC6A, NUCKS1, STAG3 and ARFRP1; (iii) markers selected from NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115; and (iv) markers selected from TRAPPC6A, NUCKS1, STAG3, ARFRP1, NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115; (c) wherein the expression or quantitatively decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease with dementia (PDD) in a patient or individual. [000134] Methods are provided wherein a blood sample is isolated and evaluated for expression or quantitatively increased or decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 27 or 28; (c) wherein the expression or quantitatively increased or decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease with dementia (PDD) in a patient or individual. [000135] A method is provided for assessing or evaluating Parkinson’s disease (PD) with dyskinesia in a patient or individual comprising: (a) isolating a sample from said patient; (b) evaluating the sample for expression or quantitatively increased or decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 20;(ii) markers as provided in Table 29 and / or 30; and (iii) markers selected from FTCDNL1, MAF1, THEM4, TSTA3, XKRX, KANSL1-AS1, NUDT15, LINC00269, TMEM80, TMPO-AS1, ALAS2, TUBB4B, AHSP, EIF3C, WDR45, KIFC3 and CDC34; (c) wherein the expression or quantitatively increased or decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) with dyskinesia in a patient or individual. [000136] Methods are provided, wherein a blood sample is isolated and evaluated for expression or quantitatively increased or decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 29 and / or 30; and (ii) markers selected from FTCDNL1, MAF1, THEM4, TSTA3, XKRX, KANSL1-AS1, NUDT15, LINC00269, TMEM80, TMPO-AS1, ALAS2, TUBB4B, AHSP, EIF3C, WDR45, KIFC3 and CDC34; (c) wherein the expression or quantitatively increased or decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) with dyskinesia in a patient or individual. [000137] A method is provided for assessing or evaluating Parkinson’s disease (PD) with disease duration in a patient or individual comprising: (a) isolating a sample from said patient; (b) evaluating the sample for expression or quantitatively increased or decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 21 an / or 22; (c) wherein the expression or quantitatively increased or decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) with dyskinesia in a patient or individual. [000138] In an embodiment of the methods, a subset of at least 20 of the markers are evaluated. In an embodiment of the methods, a subset of at least 10 of the markers are evaluated. In an embodiment of the methods, all of at least one set of the markers are evaluated. [000139] In an embodiment of the methods, RNA expression is assessed by RT PCR. In an embodiment of the methods, protein expression is assessed using specific antibodies. [000140] The mthods provided herein include further comprising treating the patient thereby diagnosed with Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), PD with dyskinesia, or PD with disease duration by administering a therapeutically effective amount of one or more agent or therapy for treating PD, dementia, or dyskinesia.[000141] Provided herein are one or more sets or a set of RNA or protein markers for assessing or evaluating Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), Parkinson’s disease dyskinesia or Parkinson’s with disease duration in a patient comprising the markers selected from: (i) markers as provided in Table 4; (ii) markers as provided in Table 13 or 14; (iii) markers as provided in Table 23, 24, 25 or 26; (iv) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4; (v) markers selected from FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (vi) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL, CAMK4, FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (vii) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4; and (viii) markers selected from FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (ix) markers as provided in Table 15, 16, 17, 18, 19, 27 or 28; (x) markers as provided in Table 27 or 28; (xi) markers selected from TRAPPC6A, NUCKS1, STAG3 and ARFRP1; (xii) markers selected from MARS1, NFAT5, LONRF3, PPP1R15B and TARS1; (xiii) markers selected from NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115; (xiv) markers selected from STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR; (xv) markers selected from TRAPPC6A, NUCKS1, STAG3, ARFRP1, NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2, TMEM115, MARS1, NFAT5, LONRF3, PPP1R15B, TARS1, STX17AS1, DACT1, DNAH8 and C1QTNF3- AMACR; (xvi) markers selected from TRAPPC6A, NUCKS1, STAG3, ARFRP1, NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115; (xvii) markers selected from MARS1, NFAT5, LONRF3, PPP1R15B, TARS1 STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR; and (xviii) markers as provided in Table 20; (xix) markers as provided in Table 29 and / or 30; and (xx) markers selected from FTCDNL1, MAF1, THEM4, TSTA3, XKRX, KANSL1-AS1, NUDT15, LINC00269, TMEM80, TMPO-AS1, ALAS2, TUBB4B, AHSP, EIF3C, WDR45, KIFC3 and CDC34; and (xxi) markers as provided in Table 21 an / or 22. [000142] In aspects or methods of the invention, the markers, RNAs, genes or their encoded proteins may be evaluated to identify or select at-risk PD patients. Thus, patients may be identified or selected,for example, for clinical trials. Provided herein are a variety of companion diagnostics and markers both for evaluating treatments, agents, compounds and for developing treatments, agents, compounds, including for different patient subsets of clinical disease, such as for PD with dementia (PDD) or PD with dyskinesia. Early and late onset PD patients may be differentially identified and assessed and can be selected for certain evaluations and clinical trials. Those at risk of different time courses (e.g. faster) for disease progression can be identified, selected and evaluated or assessed. [000143] The correlation provided herein between blood markers and changes in specific regions of the basal ganglia in the brain (caudate nucleus and putamen) may be utilized to point to or suggest specific clinical actions. This includes prescription of particular drugs or agents. This further includes the use or application of drugs or agents directed to or against one or more marker. For example, blood / brain markers may point to targeted therapies that affect the brain and therefore are potentially not just markers, but offer the potential for development or monitoring of therapeutic targets. [000144] Provided herein is a system or kit for assessing or evaluating Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), Parkinson’s disease dyskinesia or Parkinson’s with disease duration in a patient comprising a set of markers hereof or a set of probes and / or antibodies for evaluating a set of markers of hereof. [000145] Any applicable and sufficient number of markers may be evaluated in a patient to determine or evaluate, PD or aspects of PD including PDD and PD dyskinesia. Thus, the markers should be sufficient to reliably predict, assess or evaluate PD or aspects of PD including PDD and PD dyskinesia. One skilled in the art will be able to utilize the data herein and available to provide a set of markers necessary or sufficient to assess or evaluate PD or aspects of PD including PDD and PD dyskinesia. In particular and for example, markers which are associated with certain pathways or responses may be selected. [000146] A subset of at least 50 of the markers may be evaluated. A subset of at least 40 of the markers may be evaluated. A subset of at least 30 of the markers may be evaluated. A subset of at least 20 of the markers may be evaluated. A subset of at least 10 of the markers may be evaluated. A subset of at least 5 of the markers may be evaluated. A subset of at least 4 of the markers may be evaluated. A subset of at least 3 of the markers may be evaluated. At least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50 of the markers may evaluated. [000147] Evaluation of RNA or protein expression may be conducted using any method known in the art. Thus, in accordance with the methods of the invention, RNA expression may be assessed by RT PCR or may be determined by RNA sequencing. In accordance with the method, protein expression may be assessed using specific antibodies, assessing for protein activity, utilizing protein ligands. Protein expression may be evaluated utilizing one or more protein markers, such as one or more antibody specific for the protein or by a suitable readout of the amount of protein, such as a label, dye,ligand etc. Where an RNA or gene is indicated by name, its corresponding information can be derived by ne skilled in the art, such as via determination of the gene ID, a database listing, corresponding database nucleic acid or protein sequence. The sequence enables development and utilization of a nucleic acid probe, directed or specific antibody, protein assay, etc to determine expression, amount, level, activity of the corresponding nucleic acid such as RNA or of the corresponding protein. This and these approaches for evaluation of RNA or protein expression, of RNA or protein levels / amounts, or of RNA or protein activity are within the knowledge and ability of one skilled in the art. [000148] The present invention also relates to a variety of diagnostic applications, including methods for detecting and evaluating the expression of or altered presence (increased or decreased amount) of any of the markers provided herein, particularly the gene, RNA markers or their associated proteins as markers decribed and provided herein. Thus, the expression of a gene, presence or amount of RNA, or presence or amount of associated or encoded protein is evaluated. RNA may be evaluated by assessing transcriptome changes. RNA may be evaluated by RNA sequencing. RNA may be evaluated and determined by RT-PCR. Nucleic acid probes for evaluation and PCR can be designed, selected and utilized by one skilled in the art, including based on the gene and nucleic acid sequence(s) known and available corresponding to the markers listed and in the marker sets provided herein. Protein may be evaluated by reference to their ability to be recognized by a specific antbody directed thereto. Antibodies directed against the markers listed and marker sets provided herein can readily be generated using standard methods or purchased from commercial or publicly available sources. This is well within the knowledge, capability and access of the skilled artisan. For example, for the marker set GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4: anti-GPR52 antibodies are commercially available from Thermo Fisher Scientific, R&D Systems, Abcam, LS Bio, Atlas Antibodies, Sigma Aldrich and / or Santa Cruz Biotechnology; antibodies MAB10357-100 an PA5-3281, Syn211 or ab138501, PA5-26981 or ab262877, LS-C153136 or ab231634, AF5038, HPA048020 or KIAA0719, sc-393321, and ab3557 or IHC-0042 respectively. Similarly, for the marker set FCAR, PROK2, IL1R2, HSPA6 and CHRNA10: antibodies are commercially available from Thermo Fisher Scientific, R&D Systems and / or Abcam; antibodies BS-6586R or AF3939, Ab76747 or PA5-70630, PA5-21974 or 34141, PA5-21726 or ab212044 and ab234767, respectively. [000149] Proteins, peptides or peptide complexes can be identified, targeted, labeled, and / or quantitated on cells or in cells, including cell(s) in peripheral blood. Diagnostic applications include in vitro and in vivo applications well known and standard to the skilled artisan and based on the present description. Diagnostic assays and kits for in vitro assessment and evaluation of marker status or marker amounts may be utilized to diagnose, evaluate and monitor patient samples including those known to have or suspected of having Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), Parkinson’s with dyskinesia. The assessment and evaluation of PD and PD disease and associated pathologies or conditions and status is useful in determining the suitability of a patient for a clinical trial of a drug or for the administration of a particular therapy, drug, or disease agent,including as described herein, including combinations thereof, versus a different agent, drug or therapy. This type of diagnostic monitoring and assessment is already in practice utilizing antibodies against the HER2 protein in breast cancer (Hercep Test, Dako Corporation), where the assay is also used to evaluate patients for antibody therapy using Herceptin. In vivo applications may include imaging of the brain, CNS. [000150] In a further embodiment, commercial test kits suitable for use by a medical specialist may be prepared to determine the presence or absence of aberrant, differential or increased expression of one or more or of a subset of markers, genes, RNAs, relevant proteins described herein. One class of kits will contain at least the labeled marker or its binding partner, for instance a nucleic acid probe, primer, or an antibody specific thereto, and directions, of course, depending upon the method selected. The kits may also contain peripheral reagents such as buffers, stabilizers, etc. [000151] In accordance with the above, an assay system for screening potential drugs effective to modulate PD, PDD, PD dyskinesia or an aspect of PD and / or the activity of a marker or protein marker of the present invention may be prepared. The marker peptide or antibody thereto may be introduced into a test system, and the prospective drug may also be introduced into the resulting system cell culture, and the culture thereafter examined to observe any changes in the activity of the cells, binding of the antibody, or amount and extent of the marker due either to the addition of the prospective drug alone, or due to the effect of added quantities of a known agent(s). [000152] The invention provides a system or kit for evaluating PD, PDD, PD dyskinesia or an aspect of PD comprising a set of markers as described and provided herein or a set of probes and / or antibodies for evaluating a set of markers as described and provided herein. The system or kit may comprise a set of probes and / or antibodies for evaluating a set of markers selected from: (i) markers GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4; (ii) markers FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (iii) markers GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL, CAMK4, FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (iv) markers GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4; (v) markers FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (vi) markers TRAPPC6A, NUCKS1, STAG3 and ARFRP1; (vii) markers MARS1, NFAT5, LONRF3, PPP1R15B and TARS1; (viii) markers NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115; (ix) markers STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR; (x) markers TRAPPC6A, NUCKS1, STAG3, ARFRP1, NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2, TMEM115, MARS1, NFAT5, LONRF3, PPP1R15B, TARS1, STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR;(xi) markers TRAPPC6A, NUCKS1, STAG3, ARFRP1, NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115; (xii) markers MARS1, NFAT5, LONRF3, PPP1R15B, TARS1 STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR; and (xiii) markers FTCDNL1, MAF1, THEM4, TSTA3, XKRX, KANSL1-AS1, NUDT15, LINC00269, TMEM80, TMPO-AS1, ALAS2, TUBB4B, AHSP, EIF3C, WDR45, KIFC3 and CDC34. [000153] The invention may be better understood by reference to the following non-limiting Examples, which are provided as exemplary of the invention. The following examples are presented in order to more fully illustrate the preferred embodiments of the invention and should in no way be construed, however, as limiting the broad scope of the invention. EXAMPLE 1 [000154] The ability to use blood markers to predict outcomes of Parkinson’s disease (PD), including disease progression and development of cognitive and motor complications, would be of enormous clinical value. We undertook deep bulk RNA sequencing from the caudate and putamen of postmortem PD (n=35) and control (n=40) striatum, and compared molecular profiles with clinical features and bulk RNA sequencing data obtained from antemortem peripheral blood. Cognitive and motor complications of PD were associated with molecular changes in the caudate (stress response) and putamen (endothelial pathways) respectively. Later and earlier-onset PD were molecularly distinct, and disease duration was associated with distinct changes in caudate (oligodendrocyte development) and putamen (cellular senescence), respectively. Remarkably, molecular signatures and transcriptome patterns in the postmortem PD brain were also evident in antemortem peripheral blood and correlated with clinical features of disease and disease severity. Together, these findings identify molecular markers and signatures in PD patients' brain and blood of pathophysiologic and prognostic importance. [000155] Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting 2-3% of the population over 65 years of age1–3. Clinically, PD is a highly heterogeneous disease with motor symptoms such as tremors, slowness of movements, stiffness, and postural instability, and more than half of PD patients develop PD dementia (PDD) within 10 years of diagnosis4–7. Patients with late onset of PD experience faster progression and are at increased risk of dementia while patients with early onset have slower progression, less frequent cognitive impairment, but more treatment related motor complications8. The disabling motor and non- motor manifestations of PD are primarily due to loss of dopaminergic input from the substantia nigra into the dorsal striatum1. [000156] The dorsal striatum is divided into the caudate and putamen, which have discrete corticostriatal circuitry and differing roles in PD symptom manifestations9–12. Functional imagingstudies in PD patients have demonstrated that loss of dopaminergic input into the caudate and putamen correlate with cognitive impairment and motor worsening respectively13–16. While the symptomatic therapeutic mainstay for PD remains levodopa, which restores brain dopamine levels, its chronic use is fraught with several problems, including loss of drug efficacy, erratic (on-off) responses, and abnormal hyperkinetic movements such as levodopa-induced dyskinesia, a common motor complication related to dopamine transporter loss and abnormal connectivity in the putamen17,18. [000157] While the molecular basis underlying the various clinical-pathologic features of PD remain incompletely understood, a careful assessment of molecular changes following dopamine denervation in the striatum has been surprisingly limited. Two RNA sequencing (RNA-seq) studies from a small number of PD patients found downregulation of synaptic pathway RNAs in the putamen, but it is not known whether these changes are shared with the caudate or if the caudate is molecularly distinct in PD19–22. Moreover, changes in RNA in the caudate and putamen have not been studied with respect to the heterogeneous clinical features of PD. [000158] Peripheral blood transcriptome studies in Alzheimer’s disease have demonstrated correlations with clinical status, including correlates of immune and neural changes with molecular brain pathology23,24raising the question of whether the blood might be informative in PD. It has not been explored whether such correlations, particularly those associated with blood transcriptome, brain pathology and clinical status, are present in other neurologic disorders. The Parkinson’s Progression Marker Initiative (PPMI), a multi-center study aggregating whole-blood transcriptome data from PD cases and matched controls in a publicly available dataset, recently identified altered expression of immunologic signatures, with an increase in neutrophil gene expression in the whole blood of patients with PD25–27. Specifically, it is not yet known whether transcriptional changes detectable in PD blood correlate with clinical status or specific molecular changes in the brain. [000159] Here we performed RNA-seq from paired caudate and putamen regions of 35 PD and 40 control brains to develop a comparative analysis of clinical and molecular changes in PD. We identified gene expression changes that were common to both caudate and putamen, including increased levels of RNAs encoding proteins involved in regulation of miRNA activity and immune response, and decreased levels of RNAs encoding proteins involved in the postsynaptic membrane, synaptic signaling, mitochondrial dynamics and lipid metabolism. Transcriptome changes were confirmed by mass spectrometry analysis of striatal proteins. We also identified regionally distinct changes that were specific to caudate and putamen that were associated with dementia and levodopa- induced dyskinesia (motor symptoms), respectively. Later and earlier onset PD were also molecularly distinct, even at the end of their disease course. Findings in the PD brain were corroborated by analysis of bulk RNA profiles in peripheral blood obtained from the PPMI, correlating with disease severity and clinical features of the disease, and these findings were independent of medication effect. In summary, we identify molecular changes in PD caudate, putamen and blood associated with theclinical heterogeneity in PD, providing RNA markers and RNA signatures of potential pathophysiologic, diagnostic and prognostic importance. METHODS [000160] Human Samples [000161] Brain samples from individuals who had pathological confirmation of Parkinson’s disease were obtained from NIHNeuroBioBank. Control donors did not carry a clinical history of neurological disease. Chart review of available clinical material for information on age of onset / diagnosis, disease duration, medications, dementia, dyskinesia were done retrospectively from visit notes with movement disorders specialists, neurologists, general and other specialty practitioners as available. Details for categorization of individual clinical features are described in the bioinformatics section of methods. LEDD was calculated from all listed dopaminergic medications36. Relevant clinical information for blood transcriptome analysis was obtained from Parkinson’s Progression Markers Initiative (PPMI). [000162] RNA-seq [000163] RNA was extracted using standard TRIzol (Invitrogen) extraction method. RNA samples were treated with RQ1 RNase-free DNase (Promega), purified by TRIzol LS (Ambion) and checked on Agilent Bioanalyzer. The sequencing libraries were prepared for polyadenylated RNA by using Dynabeads RNA Purification Kit (ThermoFisher Scientific) and TruSeq Stranded Total RNA Gold Library Kit (Illumina) following manufacturer’s instructions. IDT for Illumina TruSeq DNA UD Indexes were used and high-throughput sequencing was performed on Illumina NovaSeq 500 to obtain 150 nucleotide paired-end reads. [000164] Mass Spectrometry [000165] Approximately 35 mg brain tissue was homogenized in 8 M urea lysis buffer (8 M urea, 100 mM Na2HPO4, pH 8.5) with HALT protease and phosphatase inhibitor cocktail (ThermoFisher). After sonication and centrifugation, protein concentration and integrity of the supernatant was tested by bicinchoninic acid (BCA) assay (Pierce) and gel electrophoresis, respectively. Disulfide bonds were reduced with dithiothreitol and cysteines alkylated with Indole acetic acid. Proteins were extracted using Chloroform / Water / Methanol precipitation and digested using LysC (Thermofisher) and trypsin. Peptides were labeled with tandem mass tag (TMT) pro labeling reagent and stoichiometry and labeling efficiency evaluated. TMT-peptides were mixed according to label check and purified using RP solid phase extraction Purified TMT-peptides were fractionated first using strong cation exchange, and then by high-pH RP-fractionation. The resulting fractions were analyzed by liquid chromatography with tandem mass spectrometry. Spectra were queried against the homo sapiens proteome concatenated with common contaminants at 1% FDR. Quantitation was performed using reporter ions from fragment spectra, requiring a spectral purity of 75%. Quantitative values for proteins were log2 transformed. A protein was required to be observed in at least 5 replicates in at least one group. Protein isoform with the highest expression was used. After this filtering, 6994(caudate) and 5183 (putamen) proteins remained. Missing values were imputed with random low- abundant values from a normal distribution. Values were normalized to the median for each channel by subtraction and significance tested using permutation-based FDR-corrected t-tests (FDR 0.05). [000166] ELISA [000167] Tissue was homogenized in Radio-immunoprecipitation (RIPA) Buffer (Sigma-Aldrich R0278) with complete Mini EDTA-free Protease Inhibitor (Roche). Protein concentration of lysate was quantified by BCA protein assay kit (Pierce).120-200 micrograms of total protein from striatum were used for quantification of Tyrosine hydroxylase using a sandwich ELISA kit (Antibodies online- ABIN6960326) according to manufacturer’s instructions. [000168] Western Blotting [000169] Protein lysates were run on NuPAGE gels (Invitrogen) and transferred to a PVDF membrane. The protein of interest was detected using ECL Prime Western Blotting Detection Reagent (Amersham - RPN2232) with an appropriate conjugated secondary HRP (1:15000) antibody. Antibodies used were: Tyrosine hydroxylase (Abcam AB112: 1:1000), GAPDH (AM4300 Invitrogen). [000170] Bioinformatics [000171] General [000172] Transcript expression was quantified from RNA-seq reads using salmon (version 0.8.1) and hg38 UCSC knownGene gene models (TxDb.Hsapiens.UCSC.hg38.knownGene, version 3.4.0). To account for differences in RNA integrity number (RIN), differential gene expression analysis was done with limma81using the voomWithQualityWeights function in order to downweight low quality samples82. GSEA analysis was performed using the fgsea R package (https: / / www.biorxiv.org / content / 10.1101 / 060012v3) using C5 gene ontology sets (https: / / www.gsea- msigdb.org), and Gene set variation analysis was performed using GSVA28. [000173] Principal component analysis (PCA) [000174] For PCA analysis, expression values from voomWithQualityWeights were corrected with the removeBatchEffect function in limma to remove effects, gender and quality (using RIN values). The top 500 variable RNAs were used for pca analysis. Kruskal-Wallis tests were performed using the correlatePCs function from the pcaExplorer package in order to test for significant correlations between PCs and experimental variables. [000175] Differential Gene and pathway expression – PD vs Control (Brain) [000176] Genes were filtered using the filterByExpr function from the edgeR package using default settings83. Samples were grouped according to brain region and disease state (PD or Control). In order to account for differences in death age in PD samples, death age was included as a covariate in the limma model. “0 + group + death age” was used as the design. voomWithQualityWeights from limma was used for normalization in order to account for sample quality. A linear model was fitted with the lmFit function, followed by computation of log2FC and moderated t-statistics with the eBayesfunction. As contrasts, PD - Control was evaluated for each brain region. Multiple hypothesis testing was performed with the decideTests function, using the “BH” method. Significant RNAs were defined as those with an FDR < 0.05 and log2FC > [0.1] or < [-0.1]. To test for LEDD-independent transcriptional changes in the brain, Control LEDD values were set to 0, and LEDD was added to the model as a continuous variable (“0 + group + death age + LEDD”). [000177] Gene set enrichment analysis - MS [000178] Gene set enrichment analysis (GSEA) was performed in order to determine GO pathways enriched in mass spectrometry data for comparing PD and control (Figure 13a). To do this, mean expression values were determined for PD and Control, and the log2 fold change values (PD / Control) were calculated from these values. For GSEA, genes were ranked according to log2 fold changes. [000179] Gene set variation analysis [000180] For all GSVA analyses, count data was processed as described for limma and log2-cpm values were obtained using the cpm function from edgeR and a prior count of 3. GSVA scores were calculated for all GO pathways with 10 or more genes in the brain or 5 or more genes in the blood with the gsva function from the GSVA package, followed by addition of sample weights with the arrayWeights function from the the limma package. The resulting scores were used for standard differential expression testing with limma as described above using the same model and contrasts as described for limma. The GSVA scores (which were calculated for all samples) were also used for plotting and t-tests among clinical subtypes using the compare_means function in the ggpubr package. [000181] Gene Ontology [000182] Enrichment of GO terms was performed by the goseq package in R84. All expressed transcripts were used as background, and gene sets were determined using log2FC and / or FDR cutoffs as described in individual figure legends. Multiple correction was performed using the p.adjust function using the Benjamini & Hochberg (“BH”) method. [000183] Classifier Genes [000184] To identify classifier genes for Parkinson’s and control patients, we used the MLSeq Bioconductor package85to implement a nearest shrunken centroid classifier on the voom variance stabilized caudate RNAseq data. We used 70% of all samples as our training set and 30% as our test dataset. The accuracy of models on test data was recorded. Following this, the accuracy of the caudate classifier was also assessed in the putamen. [000185] PPMI [000186] All transcriptome and clinical data were collected according to the PPMI study protocol (www.ppmi-info.org / access-dataspecimens / download-data). For up-to-date information on the study, visit ppmi-info.org. Transcript abundance files generated by salmon were obtained from the PPMI database. The tximport package was used to generate a count matrix86. The counts matrix filtered for the desired samples (see demographics tables) was used as input for limma and voomWithQuality weights, as described for brain samples above.[000187] Differential Gene expression – PD vs Contol (Blood) [000188] 195 healthy controls with no neurological disease and 479 subjects with primary diagnosis of PD (including 61 Scans Without Evidence of Dopaminergic Deficit, at time of inclusion) were included in our PD versus Control analysis. For each patient included in the study, sequencing and clinical information associated with only the latest study visit was used for analysis. RNA quality (defined by percent of reads mapping to the genome), gender, and age were included in the limma model to control for these variables. Age was calculated by adding age at enrollment and visit year at sample collection. GSVA analysis was performed as described above. Sequencing plate was used to determine batch. To test for LEDD-independent transcriptome changes, LEDD was also included in the limma model. [000189] Differential Gene expression – Genetic Carriers vs Control (Blood) [000190] RNA-seq data of patients with PD-relevant genetic mutations but no disease were obtained from the PPMI cohort (“Genetic unaffected”, 247 patients). Only those samples where age, quality, gender and batch information were available were included in the analysis. Most recent samples were used for analysis and compared to healthy controls (183). [000191] Differential Gene expression – PD vs Contol (Blood, Drug-Naïve Cohort) [000192] To determine PD-dependent changes in dopaminergic drug-naive PD patients, most recent RNA-seq samples when patients were drug-naive were taken into analysis. 16 subjects in the cohort whose chart did not indicate that they were drug-naive in the PPMI study were removed from analysis. For limma, gender, age, quality and batch were included in the model. For the dementia- drug naive cohort, patients who were on drugs for dementia were removed from analysis and the most recent sample when patients were drug-naive were taken for comparison (data not shown). [000193] Differential Gene expression – Dementia (Brain) [000194] PD caudate (n=35) samples were further categorized as PD dementia (PDD), PD without dementia (PD), according to clinical records. For selection of PDD and PD without dementia, a chart history of dementia (“+”) was supported by medication history for cholinesterase inhibitors or NMDA receptor antagonists for dementia or scores from a cognitive test. In those considered not to have dementia (“-”) chart reviews did not mention dementia or a medication history for dementia. One donor did not have a chart history of dementia although medication history included cholinesterase inhibitors. As Montreal cognitive assessment (MoCA) done 6 and 2 years prior to death were normal, this patient was considered to be PD without dementia. When clinical information was deemed to be inadequate for the above clinical features, the sample was removed from analysis. For DGE analysis, limma was performed as described above, using PDD, PD and Control as groups and using “0 + group + age” as the design for limma. The contrast between PDD - PD was evaluated for each brain region. Significant genes were defined as those with an FDR < [0.05] and log2FC > [0.1] or < [-0.1]. GSVA was performed as described above. [000195] Differential Gene expression – Dementia (Blood)[000196] For comparisons of cognitive impairment among the PPMI subjects, subjects with MoCa > 26 were considered to be of normal cognition, while subjects with MoCa <= 26 were considered to have cognitive impairment. Only subjects with MoCa > 26 were included among healthy controls. Limma was performed to compare PD patients with and without dementia, with age, gender, quality and batch also included in the limma model. [000197] Differential Gene expression – Dyskinesia (Brain) [000198] Patients were categorized as having levodopa-induced dyskinesia based on mention of the term upon chart review. Samples were grouped as PD-dyskinesia or PD-no dyskinesia and control. Limma was performed as described above, using PD-Dyskinesia, PD-No dyskinesia and control as groups and using “0 + group + age” as the design for limma. For comparisons, PD-Dyskinesia - PD- no dyskinesia was evaluated for each brain region. Significant genes were defined as those with an FDR < [0.1] and log2FC > [0.1] or < [-0.1]. GSVA was performed as described above. [000199] Differential Gene expression – Age of Onset (Brain) [000200] Age of onset was defined as the age of symptom onset (when available) or the age of diagnosis for each patient, whichever was the earliest information available. Samples were grouped into Control, LOPD (age of onset > than 55), or EOPD (age of onset ≤ to 55). Limma was performed as described above, accounting for death age in the model and testing EOPD - Control and LOPD - Control for each brain region. GSVA was performed as described above. [000201] Differential Gene expression – Age of Onset (Blood) [000202] EOPD and LOPD was defined among the PPMI patients as described for brain. Limma was performed to compare PD and control, using gender, quality and batch in the limma model. [000203] Pathway Analysis – Disease duration (spline interpolation, Brain) [000204] Disease duration was defined as the difference between age of symptom onset or diagnosis (as defined above) and the age of death. Spline curves were generated from the disease duration using the ns function from the splines R package (CRAN), using 4 degrees of freedom. To allow for determination of genes and GO terms with non-linear trends in the two brain regions, “X + region + region:X” was used as the design matrix, with X being the disease duration splines. For determination of genes with significant trends, voomWithQuality weights was used, followed by lmFit and eBayes, as described above. To determine significance, all coefficients corresponding to the region of interest were included in the topTable function, which generates an F-statistic and p-value. For pathway analysis, the GSVA package was used to create GSVA scores. Array weights were included in the lmFit using the arrayWeights function from limma, and the resulting object was subject to eBayes and decideTests as described above. [000205] Data Availability [000206] All demographic information and metadata are available in the Supplemental Tables. The resulting data from all relevant limma, GSEA and GSVA analyses are also included. Pathway enrichment scores, determined by GSVA, are also included. Raw data and gene expression values forbrain RNA-seq data were uploaded to GEO (GSE205450). Data used for blood transcriptome analysis in this study are available for downloading from PPMI (https: / / www.ppmi-info.org / access-data- specimens / download-data) through Laboratory of Neuro Imaging (LONI) Image Data Archive (IDA). To access the data, users need to complete a data use agreement and submit an online application. RESULTS [000207] Transcriptome Differences in PD Caudate and Putamen [000208] We undertook bulk RNA-seq from both the caudate and putamen from 40 control donors and 35 PD donors (Fig 1a, TABLE 1). TABLE 2 shows demographic characteristics and RNA quality metrics of each group. Principal component analysis (PCA) of the top 500 variable genes revealed four significant clusters, corresponding to the striatal region and clinical diagnosis (Fig 1b). The first principal component (PC1) was driven by the striatal region, separating caudate from putamen, while the second, PC2, was driven by disease status, separating control from PD striatum. PC2 scores correlated with tyrosine hydroxylase (TH) protein levels, thus confirming that these RNA changes reflected the extent of dopamine denervation in PD (Fig 2 a,b, TABLE 3). TABLE 1 D RcoA du D G P D D D A A N N A A P Liagegmgr is enoiope_atieana es dtie my nskemlldlldeueruD D D oro_B _ _ewC B ysnile oedn_ert enitneenoetpmp a p araEraa Bisiasiaiamamen th th akR o Akd edinteria o o _ _ y mloS D S glo_tLigy gytagSago catiiocmed_ _t iincancd dinaggtisedatiioagiagin on ngn g ican o o tios sissisn_s o therC C C C M C C C C N N U M S T T TR A Ae aU R R R R R RdnmA N NT A T T Tayildtag2 A AL L L L uremloe / B_ L L Llt idce32 23braar ik re / Cnab b2 lralC PU C C M 3 C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L _ L L L 2 PD C 64 23 M PD Y N Y 25 vo C 9 R d P N S A S N M A o U _e2ses / 1dar0 opb.5mivia seaarkAtag2 si e / Btageeoicdb 2 0 ma idogs / td ig e nso 42 / oC 4r raig pam n 2tex n8a / L yin' ,e se PD PU 64 23 M PD Y N Y N N N N N N N N T _es oes A A A A A A A A 22C C C C M C C C C N N b N N T T T T T TlaN n C N NT AR R R R A Araio Aryeuo triA AL U R R R L L L L L Lnrmrmte_2aolfibert ia4rilC PU C C M 24 C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _ C C C C M C C C C N N b N N N T T TR R R R R R A Araio Ailln C N NT A T T T areuo triA AL U R L L L L L Lnrm yrmte_r2aolfibet ia5 r C P C C M 5 C C C C N N N N N N N NT U T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _2 C C C C M C C C C N N b N NlarN no C N NT A T T T T T TR A A U R R R R R Rraio r Ayeut ritA AL L L L L L Ln mrme_r2aolfibet ia6rilC P C C M C C C C N N N N N N N NT U T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _26 C C C C M C C C C N N b N NlaN n C N NT A T T T T T TR A AraL U R R R R R R L L L L L Lio Arnrm yeuo triA A _ro mteri2alfiet a7brilC PU C C M C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _27 C C C C M C C C C N NicM NlaN no C N NTR A TR TR T T T T A AiniAryeut riA AL U R R R R L L L L L L _f caroro mte2rctscofibert ia8 prilC PU C C M C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _28 C C C C M C C C C N NarP N S A N NT A T T T T T TR R R R R R R A AerAtag1 A AL U L L L L L Live / B_a2s11 9cu / Cl 1 C PU C C M C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _29PD C 50 24 M PD N U N 25 L C N B L N d N no CspN M n S A o K o Ue ao oeAeF oigu _2 / 2 v rbn dw gt ri e edb 3 5 o y 0 dideyen mte c t reriifiua,stamop operat a edlla nga a / titiaPD PU 50 24 M PD N U N N N N N N N N N T _ o K o A A A A A A A A 23 PD C 6 1 F P N U N 2 L C N B L N d N n A 5 6 D 5 C oeospN pu H A o K oevaoeAgFroipm U _2 / 1 r0 obn e dywyentmitereci t s,po y 4 0 d 8 oidp oe et iafiecgd a pra / at da imala,PD PU 65 16 F PD N U N N N N N N N N N T _ o K o A A A A A A A A 24 PD C 6 5 M P N Y N 2 L C N B L N d N n C A 8 D o o5 o o AeFospN S A B ou m U _es 2 / 2evaorbn deyw gr5 50 de tmit ec tb yrainoideynerifsp oe et ia ietangdstea praat ditiaalam / ,,PD PU 68 5 M PD N Y N N N N N N N N N T _ oes o A A A A A A A A 25 PD C 8 7 M P Y U Y 2 L C A 5 D K 5ainR B L N d N n C o AeFospN Su C F o U _esesr2 / 1evarbe ivdew gtmrit eo tpron 6 0 o 0 d moid ,ast y p oiyeneericifieritextapgerat a ed o,lga amtirPD PU 85 7 M PD Y U Y N N N N N N N N T _es Kes A A A A A A A A 26 PD C 6 2 M P N U N 5 L C N B L N d N n C A 9 2 D 0 oeospN n Su A o K oevaoeAgFroigm U _ / 2 rbn dwtmit e t rb 2 0 oey yenercifa sy 7 0 d moidp oe eia ie ,tagd gapraat / t d nitiaala,PD PU 69 22 M PD N U N N N N N N N N N T _ o K o A A A A A A A A 27 PD C 8 5 M P N U N 2 L C N B L N d N n C S N A 4 D o K o5 / evaro odewAegFo tri t sapgeo U _210 obn y yemte c t8 0 d moidenp oer ert iae3ifiedgap a a / tiPD PU 84 5 M PD N U N N N N N N N N N T _ o K o A A A A A A A A 28 C C C C F C C C C N N v H TiL S A P N NT A T T T T TnoR A AL U R R R R R Reypf actaL L L L L L _e arc u glzhsA A si3rte tn ae5ei b0nr -mles6ier'C PU C C F C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _30 C C C C M C C C C N N b N N N n T T T TR A Aro AlaC N NT A T TrorA AL U R R R R R RaiL L Lnrm yeu_ L L Lr tmite3ao rlfiet ia1brilC PU C C M C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _31 C C C C F C C C C N NscA N S A N NT A T T T T T TR A AlertAta3 A AL U R R R R R RgL L L L L Lroere / B_io 53 3s2islar-6 / C3 C PU C C F C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _32 C C C C M C C C C N NsigN N S 0 1 NT A T T T T T TR R R R R R R A An o AtagaAL U L L L L L L _fi e3ca 08nt C PU C C M C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _38 C C C C M C C C C N NsigN N S 1b 0 NT A T T T T T TR R R R R A An o AtagA U R RL L L L L L L _fi3cae19nt C PU C C M C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _39 C C C C F C C C C N Nsi N N S 1 0 NT A T T T T T TR R R R A Agn o AtagaAL U R R R L L L L L L _fi4cae20nt C PU C C F C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _40 C C C C F C C C C N NsN N S 1 0 NTR A TR TR T T T T A Aign o AtagaA U R R R RL L L L L L L _fi4cae01ntC P C C F C C C C N N N N N N N NT U T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _41 C C C C F C C C C N NsiN N S 1 0 NT A T T T T T TR R A Agn o AtagaAL U R R R R R L L L _ L L Lfi e4can 02tC PU C C F C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _42 C C C C M C C C C N NsN N S 1 0 NT A T T T T T TR A Aign o AtagcA U R R R R R RL L L L L L L _fi e4ca 23nt C PU C C M C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _43 PD C 6 7 F P U U U N N P p A S N S A 5 D K Ksdl spM B N K o oaramtaota au U _3ik qygec tgeys c7recroecsoeasinu soes loe if i3 iee5nae lrisleurdrsd es n, d d t os',fPD PU 65 7 F PD U U U N N N N N N N N T _ K K K A A A A A A A A 37 PD C U U F P U U N N N P A S N S M B N A K K D K K o o osdaraxso btape ota au U _3 n 8en eisekan ungsine ci tgeeynsa cleesoald nan 1fied 3e lrit s uos't,fPD PU U U F PD U U N N N N N N N N N T K K _ K K o A A A A A A A A 38 PD C 68 7 M PD Y N Y 25 L C 5 DsP N SspN S M B N Aeoe amodaAtot au U _ ses 3 / 1 vorbg ni9 00 d moid Tepsrekageaine c t ageys cp o1ifie4nalisleupIDe / zseso edert', osga ailnfPD PU 68 7 M PD Y N Y N N N N N N N N T _es oes A A A A A A A A 39 PD C 5 2 M P Y Y N 2 L C N P N S N A 2 0 D 5sdspS M B N eeoevaoarAtot au U _ s s 4 / 1 r0 0 obni0 dskagec t ageysa clmoide ep oasine is2 fiee4n e lis eugape oa / ndrt', osfPD PU 52 20 M PD Y Y N N N N N N N N N T _eses o A A A A A A A A 40PD C 7 4 M P Y N Y 2 L C 1 D P p A S A 4 D o 5 0 osdl spN S M B N ee evararamta eota au U _ s s 4 / 1 b mnik q gtgeys c1 0 o 0 d moidgepseainu y p oe loe c1ifie4nalileupODezsi esos nid edert s, osga a / l'fPD PU 74 4 M PD Y N Y N N N N N N N N T _es oes A A A A A A A A 41 PD C 6 7 M P Y N Y 2 L C M P p A S N S A 2 D o 5e1sda l t sptM B N ese evarerama eoa e au U _ s 4 / 1 b0mik qygc tgys c2 0 o 0 d moid ma sp ogneasinu esoes,loeid 3ifieed5nael rit sleuosgap ati / nn',fPD PU 62 7 M PD Y N Y N N N N N N N N T _es oes A A A A A A A A 42 PD C 6 1 M P Y N Y 2 L C o W A 0 3 D o 5f sdP asuA SspN S L n S oigu U _eses / 2evarbfeairkbdcutageotc t agcurb 43 5 o 0 dnsmoidp oedeasinutesor e ea2ifieed4s a,stangap a / nl'tiaPD PU 60 13 M PD Y N Y N N N N N N N N T _es oes A A A A A A A A 43 PD C 5 1 M P N N Y 2 L C n R P A 7 3 D 5e sdN SspN S M B N o oe eva ivar Ata eota au U _ s 4 / 1r 4 0 ob,0 dDa is sekigne ciftgeeynsa clemoido t p oi a 1 i 4e lis upsegmseso edrt, osga a / n i 'fPD PU 57 13 M PD N N Y N N N N N N N N T _ o oes A A A A A A A A 44 PD C 52 20 F P U U U N NsPsuL SspN S L n S A D K K K o odage totoigu U _irkgsiagec t agc rb 45recroecsroeasinesotne1ifieeu4s a,standreso ivsdtsds n'e iaPD PU 52 20 F PD U U U N N N N N N N N T _ K K K A A A A A A A A 45 PD C 6 8 M P N N N 2 L C N P p A S N A 3 D o o o5eva sr odarl samtapS L n S e otaoigu U _ / 1 bnik qygc tgcurb 46 0 o 0 d moide se inue ife a,stp oapsesoesloid 2 ied 5sanga a / n'tiaPD PU 63 8 M PD N N N N N N N N N N N T _ o o o A A A A A A A A 46 PD PU U 11 M P N Y N N N N N N N N N T K D _ oeo A A A A A A A A 4s8 PD C U 11 M P N Y N 25 L C NsP NspNspN S N A K D o o odU _e aAt4s / 1evar8 0 obnreoeoa0 doide isekacsinifticeiftgeieeo6comp oeso d drgap a / nte'xC PU C C M C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _44 C C C C M C C C C N N v M N S no C N NT A T T T T T TR A Aes il Ata rA AL U R R R R R R L L L L L Lse_l d gtmitse4m 1eeriaat4llPD C 6 7 M P Y N Y E L C A 6 DeMsP N N A S N U _e1soesn teavar 10edarAspe o 2tacgeoao p dboimd misekaincift / B1e coo p ogan ssie / C 2rna / p at / in e ond' 2texPD PU 66 7 M PD Y N Y N N N N N N N N T _eo A A A A 1sesA A A A PD C 59 20 M PD Y Y Y C L C 1 D P N S A S N U _e2seses 5evar0sB A R odarAta2ta e r0 odb mnik gge se ine / B geocaoin / 2oid0 p op / d pea0a a / ayzsi eso 42 / C 4r sl ntetem' 3x, PD PU 59 20 M PD Y Y Y N N N N N N N N T _eseses A A A A A A A A 2 PD C 5 1 M P Y Y Y E L C n R A 7 4 D ne sdP a NspNspN S t N n i Su U _eseses 3t eavarcao p db 9iviroid.5astsiekAeoeoaaigeo gb ncift cift ecora,sto p o na / pga mseso ied ied 1rate n / ti n'xiaPD PU 57 14 M PD Y Y Y N N N N N N N N T _eseses A A A A A A A A 3 PD C 72 15 F P Y U N 25 L C NsP NspN A S B A D U _es K oe aodarA o 2t r4 / 1 v r0 obn 0 de iseke ai ci t / B gaein1oidp oas n fie24sap aesond / Cte3m / ' PD PU 72 15 F PD Y U N N N N N N N N N T _es K o A A A A A A A A 4 C C C C F C C C C N N A T T T T T TrA N N N N NTe spR A A g A A o A AL U R R R R R RlL L L L L Latee-ec t_difi1T eaduC PU C C F C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _1 C C C C M C C C C N N b U n R N A N NT A T T T T T TR A A U R R R R R Rlean reuareA 0 / BA AL L L L L L L _duemro2l f1 tarik b / Caril0C PU C C M C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _2 PD C 7 3 M P Y U Y d L C 1 D A 0 DeKeoeva0 osdP arcliL pe spN ospN S ot sN apo U _5s ssernodb mniikdgepseainpfitenMcift eiciftgeie cifto t op o a p / da / ayezsi esog l n',CeAd ed 5 iedPD PU 70 3 M PD Y U Y N N N N N N N N T _es Kes A A A A A A A A 5 C C C C F C C C C N N b U P N A N NTR A TR TR T T T T A Al aencuatL L L L L L LcA 0 A A U R R R Rare t_dumeh / By 2 3lt ark / Ca 0 C PU C C F C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _3 C C C C M C C C C N N b U N N A N NT A T T T T T TR R R R R R R A Alen A A 1 A AL U L L L L L La_dre / Bum1 4ltark / Ca 1 C PU C C M C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _4 C C C C M C C C C N N b U S S A N NT A T T T T T TR A Al cenomt0 A AL U R R R R R R L L L L L La_drnauemg eag / B5lnlleta31 rkti / Caal0 C PU C C M C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _5 C C C C F C C C C N N b U N S A N NT A T T T T T TR R R A Alen Atag2 A AL U R R R R L L L L L La_drueme / B6l11 tark / Ca 1 C PU C C F C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _6 C C C C F C C C C N N b U NsNsN N NT A T T T T T T A Alp pR R R Ren Aeoeo A AL U R R R L L L L L La_druemcift c t7liifitar e ek d daC P C C F C C C C N N N N N N N NT U T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _7 C C C C F C C C C N NcMaC SsN N NT A T T T T T T A AemtpR Rreo yeL L L L L Lr ageo A AL U R R R R Rbd _lebc t8roeoevraatidral 3ifieds eC PU C C F C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _8 C C C C M C C C C N N M C S A N NT A T T T T T TatR R R A Ahoamye tL L L L L Lr ag1 A AL U R R R Rerd _oer lo ebe / B11 9scleatr eidral / C1 C PU C C M C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _9 C C C C M C C C C N N b U N S A N NT A T T T T T TR R R R R R R A Alen Atag0 A AL U L L L L L Ladre / B_ ume10l11 tark / Ca 0 C PU C C M C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _10 C C C C M C C C C N N b U N N N A T T T T T TsN NTpspR R A Alen Aeoeo A AL U R R R R R L L L L L La_druemcifticifti 11lt arek d eda C P C C M C C C C N N N N N N N NT U T T T T T TR T R R R R R R A A A A A A A AL L L L _ L L L 11 PD C 61 21 F PD N U N 25 L C NsP C D N N N N A o K o / 1evarodare emo o o o U _6 0 o 0 dbnioide sekrioas n ebroenreprerereop p p5p pesovti ro r o o aan' aa, t trtrtPD PU 61 21 F PD N U N N N N N N N N N T _ o K o A A A A A A A A 6 PD C 43 23 M PD Y N Y 25 L C n RsdP N d N no CspNcon S A U _es oesevare7 / 10 ob 1ivarAegFr0 d 3a iskentmiteoid.3stieaine ereo ic t r itgu aifii recaab ,nsta2p og sesort d lona p a m / n a i 'titiaPD PU 43 23 M PD Y N Y N N N N N N N N T _es oes A A A A A A A A 7 PD C 6 1 M P Y U Y 2 L C 1 D A 8 1 D 5 0sdP NspNspN SspN es Kes / 2evarmoar Aeoeotageo U _1 5 obnikge se i ci t ci t e ci t0 0 d 1 oidp o / d peas ns fiefie 1fiea p a / ayzi e ond d d,l' PD PU 68 11 M PD Y U Y N N N N N N N N T _eK A A A A A A A 1sesA 0 C C C C M C C C C N N N N N N N NT A T T T T T TR R R R R R R A A o A o o A AL U L L L L L Lrerere_p p p1 o r o r o 2t trtC PU C C M C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _12 C C C C M C C C C N N b U N N N N NT A T T T T T TR A Al sen Apseope o A AL U R R R R R R L L L L L Ladremci t c t_ uf13ltair eifk d ieda C P C C M C C C C N N N N N N N NT U T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _13 C C C C M C C C C N N N N N N N NT A T T T T T TR R R R R R R A A o A o o A AL U L L L L L Lrerere_p p p1 o r o r o 4t trtC PU C C M C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L _ L L L 14 C C C C M C C C C N N N N N N N NT A T T T T T TR R R A A o A o o A AL U R R R R L L L L L Lreprere_1 opopo 5rtrtrt C PU C C M C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _15 C C C C M C C C C N N p R NsNsN N NT A T T T T T T A Aap pR Rr igAeoeo A AL U R R R R R L L L L L Liehc t c t_tat ifiifi1l e e6d dC PU C C M C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _16 PD C 5 2 M P Y U Y 2 L C 5 D N N N N N A 2 5 D K 5msdP aas as spsp_eses / 1evarbonirkAseo tseo teo teo U 1 0 o ge ses sci ci t1 0 did / d p ain s sf f 1 o oesso ed ed ie ie2 p a paay / zi e d dln' PD PU 52 25 M PD Y U Y N N N N N N N N T _esKesA A A A A A A A 11 PD C U U M P U U U N N A K K D K K K o osdP NspN A S N n S U _i arkAeo 2tageoigub 12recroecseaincift / Bi2ecora,staro sdrd eso ed / C 3 / 4rte nts sn' 2xiaPD PU U U M P U U U N N N N N N N N T K K D _ K K K A A A A A A A A 12 PD C 5 8 F P N N N 2 L C N A 8 D o o o5sP NsNsN S n S B U _1 / 1evar odar Ape ope otaigubr3 0 obn 0 de isekinci t ci tgera,s ain1oid afifi.5p o5tasapseso ead ed ntem / n'tia, PD PU 58 8 F PD N N N N N N N N N N N T _ o o o A A A A A A A A 13 PD C 5 1 M P Y U N 2 L C N A 8 5 D B L N d N n C K o5 o o AeFospN C n igSu U _es / 1evaorbn dew gtmrit eo ct ervrb 20 00 doidey yenee eriaifieic a,stamp o gapraat / t dal nitiaPD PU 58 15 M PD Y U N N N N N N N N N T _es K o A A A A A A A A 20 C C C C F C C C C N N o L d L S n C N w m ST A T T T T T Tfo o NR A AL U R R R R R R wisL L L L L Le eawtagsyt riemtAietr hedu,_le4v e, b 2et ialewlla5elody y C PU C C F 5 C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _4 PD C U U M PD U U U N NsP N S 5 SspN A K K _ K K K o odarkAtaga tageo U 1re re ise i e e cift5co cro as ndreso 1 3 iesds nd' PD PU U U M P U U U N N N N N N N N K D T K _ K K K A A A A A A A A 15C C C C M C C C C N N T T T TsN N S 1 0 NT A T TiR R R R R R R A Agn o AtagaAL U L L L L L Lf_i e1ca 27nt C PU C C M C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _17 C C C C M C C C C N Nsi N N S 1 0 NT A T T T T T TR R R R R R A Agn o AtagaA U RL L L L L L L _fi e1can 18tC P C C M C C C C N N N N N N N NT U T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _18 C C C C M C C C C N NsiN N S 1 R R R R R Rg0 NT A T T T T T TR A An o AtagaAL U L L L L L L _fi e1ca 29nt C PU C C M C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _19 C C C C M C C C C N N T T T T TsiN N S 1 0 NT A TR A Ago A U R R R R R R ntagaAL L L L L L L _fi2cae10nt C PU C C M C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _20 PD C 68 9 M P N N N 25 L C N B L N d N no CspN ob M P A D o o o U _1 / 1evaro oewAegFr eoeon 6 0 obn dy 0 d yentmite c t lan dsmoiderp oer et iaifieg u l,laaa dagap / titaPD PU 68 9 M PD N N N N N N N N N N N T _ o o o A A A A A A A A 16 PD C 6 6 M P U U N 2 L C N D L N d N n C N n L A 7 D K 5 U _1 / 2 v rbniswegostpmi tB K oe aoeA Frt eo ct al / imrai7 5 o 0 dide easyeneriif subnop ope, boeraet a iedpic / fsteaadytieri ro m / ,PD PU 67 6 M PD U U N N N N N N N N N T _ K K o A A A A A A A A 17C C C C M C C C C N N TsiN NspNspN N NT A T T T T TR R R A Agn o Aeoeo A AL U R R R R L L L L L Lf c t c t_i if 2ca ieif die1ntdC PU C C M C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _21 C C C C F C C C C N N T T T T TatCcM N N N NT A ThR A A U R R R R R Rheerreanildo t o t A AL L L L L L L _o bg 2s2c rloasp spevesgr -e ec ecoas re ifieifiscis ul la d edatr edC PU C C F C C C C N N N N N N N NT T T T T T TR T R R R R R R A A A A A A A AL L L L L L L _22 PD C 5 1 M P U U U N N A 4 1 D d P N n K K K o oiU _s arAo N C N L S FrA o ub 18recroeceas ktin prdite e cruis staro edrdsoesgs nesnean n co nts ' t eoerariattim uolne net uigsra,PD PU 54 11 M PD U U U N N N N N N N N T _ K K K A A A A A A A A 18 PD C 6 1 F P U U U 2 C N P N p N C N A 2 5 D K K Ktim5 U _a rL S o u 1e / 1arorAeFr9s / d0bnks 0ide in en ditA eercub say 1ois tapsotgea,tn co naba / nnL's ee ro te truian4 v dat ml igoisdeioenet uoa s raps ,e na o t PD PU 62 15 F PD U U U N N N N N N N N T _ K K K A A A A A A A A 19 TABLE 2 Controls (n=40) PD (n=35) p value Test Age at death (years) 72.4 (11.8) 76.9 (7.3) 0.0318 Wilcoxon Male / Female 28 / 12 27 / 8 0.603 (gender) Fisher test Race (White / Black / Hispanic / Other) 34 / 2 / 2 / 2 31 / 2 / 1 / 1 1 Fisher test Age of onset / diagnosis (years) NA 63 (9.2) NA Disease duration (years) NA 13.0 (6.7) NA PMI (hours) 16.9 (7.6) 18.9 (9.1) 0.45 Wilcoxon RIN (Caudate) 6.6 (1.8) 5.6 (2.0) 0.0203 WilcoxonRIN (Putamen) 6.6 (1.9) 5.5 (2.0) 0.0403 Wilcoxon Mean (standard deviation); p values were determined using listed tests TABLE 3 Sample_ID TH 2653_PD_CAU 0.66 2679_PD_CAU 0.18 2685_PD_CAU 0.72 2687_PD_CAU 0.86 2689_PD_CAU 1.51 2725_PD_CAU 0.80 2727_PD_CAU 0.47 2774_PD_CAU 0.15 2776_PD_CAU 0.01 2778_PD_CAU 0.19 2780_PD_CAU 0.42 2782_PD_CAU 0.36 2784_PD_CAU 0.28 2786_PD_CAU 0.23 2788_PD_CAU 0.31 2790_PD_CAU 0.96 2792_PD_CAU 0.30 2803_PD_CAU 0.51 2579_PD_CAU 1.82 2581_PD_CAU 0.37 2583_PD_CAU 0.52 2585_PD_CAU 3.62 2593_PD_CAU 1.33 2625_PD_CAU 0.96 2627_PD_CAU 1.58 2633_PD_CAU 0.55 2645_PD_CAU 0.29 2647_PD_CAU 1.23 2649_PD_CAU 0.85 2681_PD_CAU 0.22 2703_PD_CAU 0.20 2713_PD_CAU 0.08 2715_PD_CAU 0.29 2721_PD_CAU 0.31 2723_PD_CAU 0.13 2683_CTRL_CAU 0.16 2595_CTRL_CAU 4.11 2733_CTRL_CAU 0.84 2643_CTRL_CAU 4.42[000209] Differential gene expression analysis revealed 5383 and 5110 up and downregulated RNAs, respectively, in the PD caudate versus controls, and 5971 and 5676 up and downregulated RNAs, respectively, in PD putamen versus controls (Fig 1c, data not shown). To identify gene sets with similar biological activity that were changed in PD, we employed gene set variation analysis (GSVA) on Gene Ontology (GO) terms28(Fig 1d, data not shown). GSVA provides an enrichment analysis that takes into account all genes in a GO term / pathway using a non-parametric, unsupervised method (i.e., without relying on phenotypic / disease group information) for estimating variation of that gene set within each sample28. Both caudate and putamen showed decreases in transcripts encoding proteins involved at the synapse such as postsynaptic membrane, SNARE complex assembly, vesicular ion transport and calcium mediated signaling (Fig 1d,e), consistent with loss of dopaminergic input from the substantia nigra22,29. Other transcripts highly downregulated in the PD caudate and putamen encoded proteins involved in lipid metabolism and mitochondrial fission (Fig 1d,e), both of which are implicated in nigral dopamine neuronal dysfunction and death30,31. Conversely, regulation of miRNA activity was highly enriched indicating their role in modulation of RNA levels and translation in the PD striatum (Fig 1d,e). Pathways related to NF kappa B, a transcription factor abundantly expressed in the brain and linked to neuro-inflammation, neurogenesis and dendrite morphogenesis, were also upregulated in PD striatum (Fig 1d)32. Other immune response RNAs, including those involved in T cell activity and NOD containing-2 (NOD2) signaling pathways, were highly enriched in both regions of the striatum, indicating global immune hyperactivation in the PD brain (Fig 1d,e, data not shown). [000210] Although the majority of differentially changed GO terms were common to both caudate and putamen, we identified a number of unanticipated region-specific RNA changes (Fig 2c, Fig 1f). The caudate was characterized by increased enrichment of stress response pathways, including epigenetic pathways such as histone acetylation and methylation, protein kinase C signaling, chaperone-mediated protein folding and mitochondrial DNA metabolic process (Fig 2c, Fig 1f). Conversely, the serotonin metabolism pathway was preferentially downregulated in the caudate (Fig 2c), consistent with previous studies showing preferential loss of serotonin markers in the caudate more than putamen in PD33. Terms upregulated only in the putamen included Hedgehog signaling and connexin complex (Fig 2c)34. GO terms regulating biosynthesis of ceramides, which are substrates of the PD susceptibility gene glucocerebrosidase (GBA), were preferentially downregulated in the putamen (Fig 2c, Fig 1f)35. These results suggest that while the caudate and the putamen share common dysregulated pathways in PD, there are region-specific molecular changes, consistent with the unique roles different striatal regions have in clinical manifestations in PD. [000211] Gene ontology analysis of highly changed RNAs (TABLE 4) defined by using more stringent filters identified involvement of pathways congruent to those seen on GSVA. Downregulated terms in caudate and putamen included synaptic pathways such as trans-synapticsignaling, G protein coupled receptor signaling and postsynaptic membrane (Fig 2d). Top upregulated terms in caudate included stress response terms (cellular response to heat, chaperone-mediated protein folding), inflammatory response, and purine metabolism. In the putamen, top upregulated terms identified ion stress response as well as inflammatory response (Fig 2d).TABLE 4ID logFC P.Value adj.P.Val Region BFSP1 -1.461384 1.22E-17 1.02E-13 PUT GPCPD1 -1.3814413 2.07E-17 1.02E-13 PUT DHRS11 -1.1680176 2.16E-17 1.02E-13 PUT RBM3 -1.3144924 1.25E-16 3.68E-13 PUT PCYOX1L -1.4230596 1.22E-16 3.68E-13 PUT SLC10A4 -2.645612 1.91E-16 4.52E-13 PUT CERNA1 -1.8438493 1.36E-16 3.68E-13 PUT ANGPT2 1.676049 2.42E-15 3.29E-12 PUT ACLY -1.1845711 3.67E-15 3.87E-12 PUT NTRK1 -2.5098071 3.14E-15 3.51E-12 PUT FUCA1 -1.0994348 3.91E-15 3.91E-12 PUT CDKL1 1.23860587 4.95E-15 4.54E-12 PUT DLGAP1-AS1 1.00940568 5.97E-15 5.15E-12 PUT COL27A1 1.43027876 1.04E-14 8.21E-12 PUT H4C15 1.20079233 1.45E-14 1.00E-11 PUT CIRBP -1.1600094 2.33E-14 1.43E-11 PUT NUP210L 1.93100437 1.98E-14 1.25E-11 PUT SLC5A7 -3.5270615 2.47E-14 1.47E-11 PUT KCNE4 1.04336679 3.72E-14 1.91E-11 PUT NAA80 -1.4360332 8.96E-14 3.70E-11 PUT LPIN3 1.23731975 1.16E-13 4.40E-11 PUT DLEU7 -1.309622 1.00E-13 4.04E-11 PUT TRIP10 1.27974618 1.22E-13 4.40E-11 PUT CHODL -1.308981 1.23E-13 4.40E-11 PUT H3C15 1.77020511 1.58E-13 5.27E-11 PUT LINC00513 1.3062089 1.70E-13 5.46E-11 PUT SLCO4A1 2.70496755 2.33E-13 6.76E-11 PUT B9D1 -1.0327288 2.35E-13 6.76E-11 PUT TRPC3 -2.137579 2.29E-13 6.76E-11 PUT HHLA1 1.10094909 2.84E-13 7.83E-11 PUT TNIP2 1.02288096 3.06E-13 8.22E-11 PUT BCL6 1.16104051 3.20E-13 8.43E-11 PUT MAFF 2.02150249 3.86E-13 9.62E-11 PUT ECEL1 -2.8079175 4.46E-13 1.02E-10 PUT PNOC -2.2423085 2.13E-13 6.41E-11 PUTABCA11P -1.1956397 4.06E-13 9.76E-11 PUT LINC01561 1.37172773 4.28E-13 1.00E-10 PUT NELL1 -1.9070266 4.22E-13 1.00E-10 PUT SLC16A14 -1.0445184 5.35E-13 1.16E-10 PUT RAB11FIP1 1.03006898 5.39E-13 1.16E-10 PUT TCAP 1.34068923 5.39E-13 1.16E-10 PUT SCUBE3 1.27631731 5.54E-13 1.16E-10 PUT JMJD6 1.16170768 6.68E-13 1.36E-10 PUT PHF21B 1.06051059 6.81E-13 1.36E-10 PUT NAP1L5 -1.1163505 6.77E-13 1.36E-10 PUT MDH1 -1.3925714 7.00E-13 1.37E-10 PUT CYGB -1.5801195 8.30E-13 1.53E-10 PUT CCDC96 -1.0688772 8.43E-13 1.53E-10 PUT FLRT1 -1.0086341 9.63E-13 1.66E-10 PUT CHAT -3.4000665 7.83E-13 1.46E-10 PUT PXDC1 1.08518172 1.16E-12 1.87E-10 PUT SERTAD1 1.06484285 1.22E-12 1.93E-10 PUT CCDC184 -1.2144836 1.41E-12 2.09E-10 PUT ATP6V1G2 -1.0290694 1.38E-12 2.07E-10 PUT HOOK2 1.08072253 1.44E-12 2.11E-10 PUT ESRG 1.04959547 1.46E-12 2.13E-10 PUT LINC01338 1.81670168 1.38E-12 2.07E-10 PUT RD3 1.42543116 1.18E-12 1.89E-10 PUT SLC5A3 1.3390325 1.78E-12 2.40E-10 PUT CHRM2 -1.7300502 1.59E-12 2.29E-10 PUT PRR26 1.44021203 1.96E-12 2.58E-10 PUT PLK4 -1.5513295 9.74E-13 1.67E-10 PUT SND1-IT1 1.11314675 1.82E-12 2.43E-10 PUT KCNJ15 1.18433668 2.28E-12 2.81E-10 PUT TUBB4A -1.2569655 2.67E-12 3.11E-10 PUT LOC100506274 -2.1753694 7.87E-13 1.46E-10 PUT NXPH1 -1.5198405 3.06E-12 3.46E-10 PUT HCN4 -1.7071992 3.15E-12 3.48E-10 PUT ATOH8 1.3815879 3.50E-12 3.73E-10 PUT FAM167B 2.32989013 2.17E-12 2.75E-10 PUT ZBTB20 1.02811301 3.78E-12 3.93E-10 PUT FAM49B -1.0310387 3.96E-12 4.02E-10 PUT TNFRSF10D 1.94162385 3.82E-12 3.93E-10 PUT TAS2R4 1.05096049 4.30E-12 4.27E-10 PUT DCTN1-AS1 -1.1193487 5.23E-12 4.84E-10 PUT SLC35G5 1.65332883 4.31E-12 4.27E-10 PUT TECTA -1.3487723 5.36E-12 4.94E-10 PUTTACR1 -2.2581685 5.60E-12 5.11E-10 PUT MIR639 1.30399868 5.74E-12 5.19E-10 PUT ITFG1 -1.1665295 6.09E-12 5.43E-10 PUT ERN2 1.3392588 5.40E-12 4.96E-10 PUT NUPR1 1.39403294 6.96E-12 6.00E-10 PUT HPRT1 -1.3100857 7.03E-12 6.01E-10 PUT RELL2 -1.2249688 8.15E-12 6.73E-10 PUT NHLRC1 -1.4413045 5.64E-12 5.13E-10 PUT MIA 2.22765368 3.80E-12 3.93E-10 PUT GLTPD2 -1.4846667 6.20E-12 5.47E-10 PUT CEP152 1.11790764 9.76E-12 7.69E-10 PUT IKBKE -1.3611058 9.84E-12 7.72E-10 PUT RIPOR3 1.24296468 1.00E-11 7.81E-10 PUT IL21R 1.14979411 1.13E-11 8.62E-10 PUT LNP1 -1.0838769 1.14E-11 8.63E-10 PUT PRPS2 -1.1339262 1.21E-11 9.00E-10 PUT DYNC1I1 -1.0411968 1.32E-11 9.57E-10 PUT CFLAR-AS1 1.14168205 1.26E-11 9.30E-10 PUT AMBN -3.3143947 9.72E-12 7.69E-10 PUT GOLGA8J -1.3468397 1.45E-11 1.02E-09 PUT C5orf17 1.25047538 1.58E-11 1.09E-09 PUT FLJ31356 1.53111274 8.94E-12 7.23E-10 PUT GPR4 1.88549942 1.62E-11 1.11E-09 PUT KCNK6 1.1013542 1.63E-11 1.11E-09 PUT TUBB3 -1.3096493 1.67E-11 1.13E-09 PUT LINC01722 1.13851432 1.72E-11 1.16E-09 PUT LINC00838 1.40061336 1.23E-11 9.10E-10 PUT MS4A2 1.00581487 1.43E-11 1.02E-09 PUT MT1E 1.24979199 1.96E-11 1.27E-09 PUT NMBR -2.2643367 6.16E-12 5.46E-10 PUT KAZALD1 -1.2010685 1.38E-11 9.88E-10 PUT SPR 1.35717748 2.14E-11 1.36E-09 PUT FFAR2 1.16639428 1.96E-11 1.27E-09 PUT GABARAPL1 -1.0490172 2.18E-11 1.37E-09 PUT LINC01087 1.13575144 2.23E-11 1.38E-09 PUT EXOC3L1 -1.2073872 1.82E-11 1.21E-09 PUT MT1M 1.63283081 2.24E-11 1.38E-09 PUT DEPP1 2.14238474 2.26E-11 1.38E-09 PUT STC1 1.97756115 2.18E-11 1.37E-09 PUT GPRC5A 1.63167495 2.38E-11 1.43E-09 PUT PPP1R18 1.04958871 2.33E-11 1.41E-09 PUT PDP1 -1.5129021 2.31E-11 1.41E-09 PUTMALAT1 1.3970147 2.44E-11 1.45E-09 PUT LINC02547 1.06034161 2.48E-11 1.46E-09 PUT C9orf153 1.83213874 1.27E-11 9.31E-10 PUT NUDT18 -1.0814856 2.97E-11 1.68E-09 PUT FOSL1 1.27963304 2.80E-11 1.62E-09 PUT EGR2 -2.0241983 2.93E-11 1.66E-09 PUT C7orf61 1.94921341 3.27E-11 1.79E-09 PUT MT2A 1.29672763 3.35E-11 1.83E-09 PUT PAK1 -1.1433171 3.28E-11 1.80E-09 PUT WDR78 1.2060133 3.42E-11 1.85E-09 PUT LOC101928118 1.00637001 3.73E-11 1.96E-09 PUT LINC02078 1.17607579 3.76E-11 1.97E-09 PUT MRPS6 1.03330042 3.81E-11 1.98E-09 PUT ELFN1 -1.1618662 4.02E-11 2.03E-09 PUT GPRASP2 -1.0782237 3.93E-11 2.01E-09 PUT XK -1.4797702 4.30E-11 2.13E-09 PUT LINC02288 1.46324371 4.27E-11 2.12E-09 PUT HAPLN1 -1.8085186 3.64E-11 1.94E-09 PUT LINC02245 1.34874335 4.82E-11 2.31E-09 PUT NXPH2 -2.4472725 1.21E-11 9.00E-10 PUT DPPA4 1.31494582 4.71E-11 2.28E-09 PUT MPO -1.4722618 3.70E-11 1.96E-09 PUT PTPRN2 -1.3952949 5.41E-11 2.53E-09 PUT PPM1E -1.1446398 5.65E-11 2.60E-09 PUT CTRC 1.39279437 4.36E-11 2.14E-09 PUT SHANK2-AS3 1.21426542 5.30E-11 2.49E-09 PUT ARL4D -1.5223752 5.73E-11 2.62E-09 PUT PCLAF 1.43063748 5.77E-11 2.63E-09 PUT ADAMTS9- 1.09213241 5.77E-11 2.63E-09 PUT AS2 BZW2 -1.0679605 5.83E-11 2.63E-09 PUT LHX8 -2.6725967 4.87E-11 2.32E-09 PUT SKOR1 -1.4095403 3.93E-11 2.01E-09 PUT DCAF12L2 -2.0670772 2.76E-11 1.60E-09 PUT ATP5MGL 1.32786997 4.87E-11 2.32E-09 PUT NFKB2 1.01056892 6.28E-11 2.76E-09 PUT LINC02071 1.27237441 4.62E-11 2.25E-09 PUT CX3CL1 -1.2944677 6.20E-11 2.73E-09 PUT ASAH2 -1.0615768 6.55E-11 2.85E-09 PUT LOC101928123 1.3943623 5.56E-11 2.57E-09 PUT SPINK9 1.38611978 7.26E-11 3.06E-09 PUT PLAC8 1.15656192 7.14E-11 3.03E-09 PUT LOC101928855 1.42555253 5.85E-11 2.64E-09 PUTNOS1 -1.2687551 7.57E-11 3.15E-09 PUT ME3 -1.1559327 7.82E-11 3.23E-09 PUT NUGGC 1.23876544 8.32E-11 3.33E-09 PUT MAB21L3 1.41999487 8.01E-11 3.25E-09 PUT TJP3 1.36158671 7.99E-11 3.25E-09 PUT CLEC2B 1.4702124 8.80E-11 3.47E-09 PUT H1-2 1.26241633 9.41E-11 3.66E-09 PUT C5orf63 1.0020125 9.44E-11 3.66E-09 PUT FOXJ1 2.25933673 9.49E-11 3.67E-09 PUT PCAT19 1.44652512 9.75E-11 3.75E-09 PUT TGFB2-OT1 1.27579742 9.97E-11 3.81E-09 PUT CMPK2 -1.0926632 1.00E-10 3.84E-09 PUT PRICKLE2- 1.12350395 9.16E-11 3.58E-09 PUT AS3 GCNT3 1.18975614 9.61E-11 3.70E-09 PUT LHX6 -1.2413143 1.08E-10 4.05E-09 PUT HTR3B 1.00635622 1.06E-10 4.02E-09 PUT CCDC102A 1.40605259 1.07E-10 4.03E-09 PUT CALM3 -1.2351077 1.19E-10 4.39E-09 PUT MT1F 1.54326253 1.14E-10 4.24E-09 PUT MRPL23-AS1 -1.467408 1.08E-10 4.05E-09 PUT CCBE1 1.31937795 1.28E-10 4.60E-09 PUT MIR497 1.1126452 1.13E-10 4.22E-09 PUT GOT1 -1.1145771 1.27E-10 4.58E-09 PUT LOC283038 1.6871967 1.33E-10 4.73E-09 PUT PRKX 1.24969876 1.45E-10 5.08E-09 PUT CYP2C8 -1.5801331 1.25E-10 4.54E-09 PUT PAM -1.0780218 1.57E-10 5.37E-09 PUT LIPH 1.06327349 1.52E-10 5.27E-09 PUT BTBD19 1.10428264 1.67E-10 5.64E-09 PUT MCM8-AS1 1.07786616 1.47E-10 5.16E-09 PUT GPD1 -1.553571 1.69E-10 5.70E-09 PUT LOC101927476 1.18993218 1.59E-10 5.44E-09 PUT PPEF2 1.0723835 1.55E-10 5.35E-09 PUT TMEM179 -1.5884019 1.77E-10 5.86E-09 PUT GKAP1 1.15520779 1.73E-10 5.77E-09 PUT LRG1 1.2582499 1.52E-10 5.28E-09 PUT SLC7A4 -1.8586128 1.71E-10 5.73E-09 PUT CCDC36 1.38052337 1.56E-10 5.35E-09 PUT IGSF3 -1.11416 1.90E-10 6.17E-09 PUT LINC02261 1.20679395 1.66E-10 5.62E-09 PUT MKNK2 1.1939388 1.99E-10 6.41E-09 PUT C2orf80 -1.364353 2.20E-10 6.98E-09 PUTFAR2 -1.0816488 2.24E-10 7.02E-09 PUT FOXP1-AS1 1.16686807 1.70E-10 5.73E-09 PUT ZFP42 1.09091722 2.18E-10 6.93E-09 PUT YBX3 1.06221034 2.24E-10 7.02E-09 PUT SPON2 -1.2022943 2.47E-10 7.51E-09 PUT RCAN2 -1.3486843 2.35E-10 7.27E-09 PUT ENO2 -1.097156 2.52E-10 7.61E-09 PUT FAM163B -1.7057977 2.70E-10 8.02E-09 PUT CSRP3 1.88205349 7.17E-11 3.03E-09 PUT MOGAT3 1.09164826 2.60E-10 7.82E-09 PUT CLLU1 1.48333227 1.78E-10 5.86E-09 PUT CHORDC1 1.36613233 2.63E-10 7.88E-09 PUT SMIM31 1.13531302 2.63E-10 7.86E-09 PUT SPACA6 1.0131215 3.01E-10 8.75E-09 PUT ZNF341-AS1 2.05924963 6.11E-11 2.70E-09 PUT REP15 1.61897645 1.94E-10 6.27E-09 PUT RFPL1 -1.5475055 3.18E-10 9.15E-09 PUT CLDN15 1.01010595 3.25E-10 9.29E-09 PUT HS6ST2 -1.8274841 3.45E-10 9.70E-09 PUT HIF3A 1.10162389 3.23E-10 9.26E-09 PUT RHOH 1.11402306 3.15E-10 9.09E-09 PUT TOMM70 -1.1851745 3.41E-10 9.63E-09 PUT SPHKAP -1.6385925 3.65E-10 1.02E-08 PUT FAM92B 1.65485616 3.70E-10 1.03E-08 PUT NEAT1 1.5862602 3.82E-10 1.06E-08 PUT LHFPL3 -1.3455677 4.02E-10 1.10E-08 PUT VSIR 1.12138096 3.93E-10 1.08E-08 PUT LOC441086 -1.21014 3.87E-10 1.07E-08 PUT LRRC17 -1.3245079 3.26E-10 9.29E-09 PUT DSCAM-AS1 1.56806475 3.74E-10 1.04E-08 PUT C10orf126 1.21852894 4.02E-10 1.10E-08 PUT SCG5 -1.3817658 4.20E-10 1.13E-08 PUT CYP26A1 -2.4473054 2.22E-10 7.01E-09 PUT PPIAL4G 1.13551276 4.53E-10 1.20E-08 PUT RASGRF1 -1.2838112 4.32E-10 1.16E-08 PUT HRG 1.55784244 4.33E-10 1.16E-08 PUT POU2AF1 1.26509304 4.46E-10 1.19E-08 PUT LOC284009 1.01833599 4.74E-10 1.24E-08 PUT SLC18A3 -2.4351107 4.67E-10 1.22E-08 PUT KCNA7 1.06203918 4.64E-10 1.22E-08 PUT OTX2-AS1 1.45281201 5.10E-10 1.32E-08 PUT NPFF 1.01069428 5.14E-10 1.32E-08 PUTPPP4R4 -1.2411869 5.18E-10 1.33E-08 PUT ADAMTS8 -1.0095538 5.48E-10 1.39E-08 PUT SHOC1 1.15671798 5.61E-10 1.42E-08 PUT CNR2 1.16571974 5.44E-10 1.39E-08 PUT ADAMTSL3 1.11425008 5.47E-10 1.39E-08 PUT C21orf62 1.35106513 6.23E-10 1.53E-08 PUT SLC17A8 -1.7992438 5.98E-10 1.48E-08 PUT MAGEE1 -1.4469652 5.86E-10 1.46E-08 PUT GCNA 1.14280858 6.30E-10 1.54E-08 PUT MARCHF3 1.0177924 6.40E-10 1.56E-08 PUT CYP4X1 -1.2036852 6.71E-10 1.62E-08 PUT NLRP8 1.77613898 3.25E-10 9.29E-09 PUT SNORD17 1.57515011 6.60E-10 1.60E-08 PUT ZBTB16 1.39680665 6.81E-10 1.64E-08 PUT BAZ1A 1.03690112 7.00E-10 1.67E-08 PUT TNFSF14 1.1583152 7.05E-10 1.68E-08 PUT DCLK1 -1.0738205 7.29E-10 1.73E-08 PUT LOC105369507 2.17999984 2.67E-10 7.94E-09 PUT SLC15A1 1.31324722 7.68E-10 1.79E-08 PUT SH3RF2 -1.8115404 7.78E-10 1.81E-08 PUT CCDC188 -1.2102776 7.58E-10 1.77E-08 PUT SLC7A11-AS1 1.73051841 7.89E-10 1.83E-08 PUT SKA1 1.13951841 8.50E-10 1.92E-08 PUT LINC00691 1.07438891 7.95E-10 1.83E-08 PUT SOX1-OT -1.4299883 9.17E-10 2.04E-08 PUT GPR61 -1.2427144 9.26E-10 2.05E-08 PUT NBPF10 1.2359096 8.48E-10 1.92E-08 PUT SST -2.178769 8.74E-10 1.96E-08 PUT MIR193BHG -1.2856926 9.13E-10 2.04E-08 PUT FIBCD1 -1.7640982 7.62E-10 1.78E-08 PUT NUDT10 -1.1664177 1.00E-09 2.18E-08 PUT LINC01609 1.0737827 9.47E-10 2.09E-08 PUT TARM1 1.73975012 8.68E-10 1.95E-08 PUT LRPAP1 -1.0194464 1.00E-09 2.18E-08 PUT ERC2-IT1 1.2596926 9.18E-10 2.04E-08 PUT PIM1 1.13828268 1.04E-09 2.25E-08 PUT WNT16 -2.2524393 7.40E-10 1.74E-08 PUT C22orf34 1.04605554 1.09E-09 2.31E-08 PUT DDIT4 1.50008489 1.01E-09 2.19E-08 PUT LINC02584 1.07784948 9.18E-10 2.04E-08 PUT CLEC1A 1.06400227 1.11E-09 2.36E-08 PUT TUSC3 -1.2786443 1.05E-09 2.26E-08 PUTSUSD1 -1.0533724 1.15E-09 2.41E-08 PUT DUSP2 -1.4180197 1.18E-09 2.46E-08 PUT SMIM10L2B -1.2258424 1.11E-09 2.36E-08 PUT EDN3 -1.4291797 1.19E-09 2.48E-08 PUT ROBO2 -1.2629512 1.11E-09 2.36E-08 PUT PCDHAC2 -1.2050651 1.17E-09 2.46E-08 PUT RNF112 -1.1398479 1.12E-09 2.37E-08 PUT RRM2 1.02945222 1.11E-09 2.36E-08 PUT PCSK1 -1.8234452 1.27E-09 2.63E-08 PUT LINC01873 1.24484105 1.15E-09 2.43E-08 PUT MYBPC1 1.22766739 1.17E-09 2.45E-08 PUT LOC101928909 1.31831679 1.04E-09 2.23E-08 PUT LRRC73 -1.1005055 1.33E-09 2.70E-08 PUT P2RY12 -1.5010355 1.37E-09 2.76E-08 PUT SLC7A3 -2.145565 6.65E-10 1.61E-08 PUT NCR3LG1 -1.1011122 1.41E-09 2.82E-08 PUT CEBPD 1.73741752 1.34E-09 2.72E-08 PUT NEK2 1.06989002 1.30E-09 2.67E-08 PUT CRABP2 -1.4521025 1.44E-09 2.86E-08 PUT RNF128 -1.4121977 1.41E-09 2.82E-08 PUT RBM47 1.10392503 1.45E-09 2.87E-08 PUT IFITM2 1.32071844 1.33E-09 2.70E-08 PUT CRYM-AS1 1.05535858 1.31E-09 2.69E-08 PUT TRPV6 -1.2110989 1.50E-09 2.94E-08 PUT GCM1 1.24471861 1.32E-09 2.69E-08 PUT NPY5R -1.7726254 1.52E-09 2.97E-08 PUT GPR52 -2.3727388 1.47E-09 2.91E-08 PUT LINC01588 1.07457867 1.58E-09 3.04E-08 PUT HAS2-AS1 1.39110524 1.28E-09 2.64E-08 PUT GOLGA6L6 1.11183207 1.57E-09 3.04E-08 PUT ADAMTS9 1.73577601 1.61E-09 3.08E-08 PUT BCYRN1 1.20338249 1.66E-09 3.14E-08 PUT CASP4 1.0474613 1.71E-09 3.18E-08 PUT ATAD3C 1.30547416 1.69E-09 3.16E-08 PUT TBC1D30 -1.0222724 1.71E-09 3.19E-08 PUT PCA3 1.00254876 1.82E-09 3.35E-08 PUT ZCCHC12 -1.6749605 1.73E-09 3.22E-08 PUT ACOT7 -1.1284309 1.67E-09 3.14E-08 PUT RASGRP2 -1.2754515 1.68E-09 3.15E-08 PUT ABCG4 -1.1364723 1.84E-09 3.37E-08 PUT VGF -1.991578 1.76E-09 3.26E-08 PUT PNMA3 -1.1899783 1.77E-09 3.27E-08 PUTBMP4 1.35212965 1.70E-09 3.18E-08 PUT HOXB13 1.45286188 1.92E-09 3.49E-08 PUT HRH4 1.04524915 1.88E-09 3.42E-08 PUT SMOC2 -1.1042406 1.92E-09 3.48E-08 PUT KCNAB1 -1.7561407 1.83E-09 3.36E-08 PUT LOC102724163 1.31986253 1.89E-09 3.44E-08 PUT RTN1 -1.2737114 1.91E-09 3.47E-08 PUT C17orf107 -1.2388075 2.04E-09 3.64E-08 PUT DRD5 -1.5600764 1.96E-09 3.54E-08 PUT RGS7 -1.3307134 1.93E-09 3.49E-08 PUT OLFM3 -1.6030065 2.10E-09 3.71E-08 PUT CLSTN3 -1.5912473 2.01E-09 3.59E-08 PUT LINC01134 1.35309526 1.44E-09 2.85E-08 PUT HTR6 -2.2367004 2.30E-09 3.99E-08 PUT ARHGEF9 -1.1310253 2.15E-09 3.77E-08 PUT MIR202HG 1.36685567 1.64E-09 3.10E-08 PUT HSPB1 1.97311668 2.27E-09 3.94E-08 PUT RAB13 1.00771737 2.21E-09 3.85E-08 PUT CLEC2L -1.3228159 2.46E-09 4.20E-08 PUT INSYN1-AS1 -1.6053156 1.62E-09 3.09E-08 PUT RIT2 -1.3711945 2.50E-09 4.24E-08 PUT CD3G 1.16292173 2.37E-09 4.09E-08 PUT MLKL 1.42927583 2.50E-09 4.24E-08 PUT ZBED6 1.12898048 2.43E-09 4.16E-08 PUT SMIM25 1.03924588 2.41E-09 4.12E-08 PUT GLP1R -2.055884 1.95E-09 3.51E-08 PUT BATF -1.6940028 2.18E-09 3.81E-08 PUT KIRREL3-AS2 1.48213626 2.60E-09 4.37E-08 PUT DOCK9-DT -1.4156807 2.06E-09 3.67E-08 PUT STXBP1 -1.1557743 2.56E-09 4.31E-08 PUT LINC01133 1.52124479 2.74E-09 4.53E-08 PUT BNIPL 1.0486563 2.53E-09 4.26E-08 PUT GPRACR 1.23398351 2.18E-09 3.81E-08 PUT LINC01119 -1.5612283 2.09E-09 3.71E-08 PUT PADI1 -1.8639254 1.37E-09 2.76E-08 PUT LDB2 -1.24169 2.64E-09 4.41E-08 PUT HROB 1.2867426 2.61E-09 4.39E-08 PUT BAG3 1.67186151 2.71E-09 4.49E-08 PUT NSG1 -1.6539715 2.74E-09 4.53E-08 PUT CCR4 1.00619411 2.93E-09 4.78E-08 PUT SIGLEC1 -1.2307649 2.98E-09 4.83E-08 PUT EVC2 1.35632222 2.89E-09 4.74E-08 PUTPSMD6-AS2 1.04932025 2.86E-09 4.70E-08 PUT RNF222 1.08239692 2.50E-09 4.24E-08 PUT H3C4 1.36561892 2.51E-09 4.25E-08 PUT SLC36A2 1.08348486 3.25E-09 5.16E-08 PUT KLHL13 -1.4696362 3.16E-09 5.04E-08 PUT NSF -1.4278281 3.24E-09 5.16E-08 PUT UPK2 -1.6610615 1.85E-09 3.37E-08 PUT LINC00638 1.0744679 3.74E-09 5.73E-08 PUT AICDA 1.12815546 3.65E-09 5.63E-08 PUT RAB3A -1.6103503 3.62E-09 5.60E-08 PUT LOC158434 1.31845193 3.71E-09 5.69E-08 PUT ATP1A1 -1.0851442 3.95E-09 6.02E-08 PUT CYP4F8 1.00771517 4.12E-09 6.20E-08 PUT POU2F3 1.42474264 3.96E-09 6.02E-08 PUT CORT -1.769427 4.07E-09 6.14E-08 PUT ANKRD22 1.1103244 4.12E-09 6.20E-08 PUT RNU6-1 1.95271919 4.15E-09 6.24E-08 PUT FAM151A 1.1166503 4.74E-09 6.91E-08 PUT SIAH3 -1.0764757 4.99E-09 7.22E-08 PUT TPBGL -1.6137523 5.02E-09 7.25E-08 PUT LINC00470 1.69902228 3.10E-09 4.96E-08 PUT UBE2T -1.1920455 5.56E-09 7.91E-08 PUT LINC01310 -1.4091488 5.64E-09 7.99E-08 PUT TAC3 -1.737523 5.90E-09 8.30E-08 PUT CCL5 1.14448994 6.02E-09 8.43E-08 PUT NPAS4 -2.8037212 4.77E-09 6.94E-08 PUT CEL 1.04812573 5.96E-09 8.36E-08 PUT TNFRSF1A 1.05284885 5.65E-09 8.00E-08 PUT BACE2 1.1334717 6.34E-09 8.80E-08 PUT OSBPL10-AS1 1.27666032 4.03E-09 6.10E-08 PUT GLT1D1 -1.4142394 6.10E-09 8.52E-08 PUT PLPPR4 -1.5443745 5.84E-09 8.24E-08 PUT SYTL1 1.0674305 6.32E-09 8.78E-08 PUT LRRTM1 -1.2708002 6.21E-09 8.64E-08 PUT LOC101927560 1.37323589 6.43E-09 8.88E-08 PUT GPR82 1.11765365 7.32E-09 9.83E-08 PUT LOC101927661 1.34531346 5.61E-09 7.96E-08 PUT ST7-AS1 -1.4075215 5.14E-09 7.42E-08 PUT NLRP12 1.05819107 6.89E-09 9.39E-08 PUT SERPINH1 2.20172948 6.96E-09 9.44E-08 PUT CLVS1 -1.4321457 7.34E-09 9.84E-08 PUT LOC101929698 1.02097983 7.42E-09 9.92E-08 PUTOPCML -1.322099 6.92E-09 9.41E-08 PUT MCHR1 -1.7906075 6.36E-09 8.82E-08 PUT ADIPOQ 1.29443098 7.11E-09 9.61E-08 PUT MC4R -2.2807596 7.49E-09 9.99E-08 PUT MSX1 1.39591321 8.06E-09 1.06E-07 PUT LOC389641 1.15726575 6.42E-09 8.87E-08 PUT CACNA2D2 -1.1708394 7.25E-09 9.77E-08 PUT LINC01006 -1.2755761 7.34E-09 9.85E-08 PUT PRR27 1.18780232 5.98E-09 8.37E-08 PUT BLACE 1.27704805 4.97E-09 7.21E-08 PUT PGM5P2 1.06532465 8.16E-09 1.07E-07 PUT RTN4RL1 -1.2119088 8.41E-09 1.10E-07 PUT ART4 1.14047339 6.78E-09 9.28E-08 PUT CDH22 -1.1480743 8.25E-09 1.08E-07 PUT DNASE1L3 1.22215402 8.66E-09 1.13E-07 PUT KCNJ6 1.34496991 7.96E-09 1.05E-07 PUT NBPF14 1.38318394 7.95E-09 1.05E-07 PUT RDH12 -1.0204916 8.07E-09 1.06E-07 PUT OLAH 1.08258718 7.87E-09 1.04E-07 PUT SPEF1 -1.1242232 8.88E-09 1.15E-07 PUT PREPL -1.0658077 9.24E-09 1.19E-07 PUT FBN3 -1.1422551 9.06E-09 1.17E-07 PUT ZC3H12A 1.27916974 9.36E-09 1.20E-07 PUT LILRA5 1.53602083 9.04E-09 1.17E-07 PUT PATE2 1.01254605 1.01E-08 1.27E-07 PUT NBPF20 1.29750814 9.54E-09 1.21E-07 PUT CLSTN2 -1.2697106 9.99E-09 1.26E-07 PUT ADAM11 -1.0827509 1.06E-08 1.33E-07 PUT WASF1 -1.3436625 1.00E-08 1.26E-07 PUT SERPINB11 1.69882826 6.73E-09 9.22E-08 PUT NEXN-AS1 1.31252798 1.14E-08 1.41E-07 PUT PNISR 1.01253307 1.03E-08 1.30E-07 PUT TMEM30B -1.1237471 1.09E-08 1.36E-07 PUT WNT9B 1.02830551 1.06E-08 1.33E-07 PUT MAL2 -1.6869198 1.06E-08 1.33E-07 PUT TUBA8 -1.4064924 1.09E-08 1.36E-07 PUT RAX2 1.25756762 9.48E-09 1.21E-07 PUT CD96 1.32969485 1.15E-08 1.42E-07 PUT CRAT37 1.09397846 1.18E-08 1.44E-07 PUT SOCS3 2.35835839 1.18E-08 1.45E-07 PUT ADRA1D -1.2344336 1.17E-08 1.44E-07 PUT KLK11 1.18132795 1.22E-08 1.48E-07 PUTTRPC7 -1.8488106 6.71E-09 9.20E-08 PUT CALN1 -1.0385779 1.13E-08 1.40E-07 PUT MPEG1 -1.1737888 1.29E-08 1.55E-07 PUT CGAS 1.0029712 1.30E-08 1.56E-07 PUT GATA2-AS1 1.32396917 1.22E-08 1.48E-07 PUT SLC10A1 1.61429557 9.47E-09 1.21E-07 PUT DIRAS2 -1.4841632 1.20E-08 1.46E-07 PUT PLAC4 1.30177558 1.36E-08 1.62E-07 PUT PIGR 1.11490321 1.35E-08 1.60E-07 PUT RNU11 1.76700413 1.34E-08 1.59E-07 PUT LINC00410 1.03176646 1.30E-08 1.56E-07 PUT KDM4D -1.1582233 1.23E-08 1.49E-07 PUT GLRB -1.007699 1.29E-08 1.54E-07 PUT EGR1 -1.190558 1.28E-08 1.54E-07 PUT SLC13A4 1.00638288 1.51E-08 1.76E-07 PUT STAM-AS1 1.03735678 1.33E-08 1.58E-07 PUT GGT6 1.2093982 1.47E-08 1.72E-07 PUT NDC80 1.18253354 1.59E-08 1.83E-07 PUT APELA 1.0560249 1.39E-08 1.64E-07 PUT NPTN -1.2708788 1.53E-08 1.77E-07 PUT FAM9A 1.53984006 1.48E-08 1.73E-07 PUT AP1S1 -1.0409059 1.57E-08 1.81E-07 PUT LINC00562 1.00240214 1.69E-08 1.93E-07 PUT NEBL-AS1 -1.4077932 1.30E-08 1.55E-07 PUT L1TD1 1.29731528 1.87E-08 2.09E-07 PUT NOTO 1.11345434 1.25E-08 1.51E-07 PUT TAGLN3 -1.5753237 1.66E-08 1.90E-07 PUT NPC1L1 1.91135584 1.40E-08 1.66E-07 PUT TNFSF8 -1.3725362 1.16E-08 1.43E-07 PUT ZSCAN4 1.11907827 1.96E-08 2.18E-07 PUT SORCS3 -1.1365702 1.96E-08 2.17E-07 PUT SDR16C5 -1.3559307 1.89E-08 2.11E-07 PUT LCN10 2.15756233 1.47E-08 1.71E-07 PUT LINC00311 1.52119112 2.05E-08 2.25E-07 PUT FAM156B -2.930958 2.16E-08 2.35E-07 PUT EXTL1 -1.0088263 2.05E-08 2.25E-07 PUT ARHGAP20 -1.2773384 2.08E-08 2.28E-07 PUT NETO1 -1.467127 2.10E-08 2.29E-07 PUT LOC101929586 1.036774 2.27E-08 2.42E-07 PUT B3GNT2 -1.0579026 2.04E-08 2.24E-07 PUT KCNK2 -1.4114459 2.20E-08 2.38E-07 PUT SYS1- -1.2787943 2.43E-08 2.55E-07 PUT DBNDD2CABCOCO1 -1.2879967 2.45E-08 2.58E-07 PUT PRKCD -1.0517357 2.17E-08 2.35E-07 PUT GNG3 -1.0566106 2.16E-08 2.35E-07 PUT C9orf129 -1.5243565 2.01E-08 2.22E-07 PUT C10orf82 1.07461753 2.60E-08 2.70E-07 PUT VWA7 -1.4044822 2.57E-08 2.66E-07 PUT HSPB9 1.08745228 2.29E-08 2.44E-07 PUT C5orf60 1.00068211 2.43E-08 2.56E-07 PUT SERTM1 -2.0651358 2.19E-08 2.37E-07 PUT GS1-279B7.1 1.04100436 2.25E-08 2.41E-07 PUT PCDHGC5 -1.9229533 2.50E-08 2.61E-07 PUT LOC101928622 1.8646001 1.17E-08 1.43E-07 PUT KIAA1210 1.08271752 2.46E-08 2.58E-07 PUT C11orf97 -1.491093 2.59E-08 2.69E-07 PUT PCDHGC4 -1.0180183 2.84E-08 2.90E-07 PUT NNAT -1.7074759 2.63E-08 2.72E-07 PUT PRSS56 -1.484683 2.33E-08 2.48E-07 PUT ALB -1.4805083 2.30E-08 2.45E-07 PUT CEACAM8 1.00112639 2.77E-08 2.84E-07 PUT NPY -1.9455449 2.71E-08 2.80E-07 PUT B4GALT6 -1.0540617 2.72E-08 2.80E-07 PUT ZNF20 1.09650754 3.18E-08 3.16E-07 PUT CAPN12 1.37592919 2.94E-08 2.97E-07 PUT LPL -1.6157839 3.01E-08 3.03E-07 PUT SLC12A3 1.69416741 2.56E-08 2.66E-07 PUT CELSR1 1.56930707 3.58E-08 3.51E-07 PUT SMIM17 -1.2484268 3.43E-08 3.38E-07 PUT ATP2B3 -1.2790627 3.10E-08 3.10E-07 PUT MYOG 1.42840376 3.11E-08 3.11E-07 PUT PNMA2 -1.045662 3.35E-08 3.31E-07 PUT MAP3K5-AS1 1.09752301 3.27E-08 3.23E-07 PUT PHF24 -1.3349167 3.46E-08 3.40E-07 PUT RBM5-AS1 1.12159011 3.67E-08 3.58E-07 PUT PRAG1 -1.0229277 3.52E-08 3.45E-07 PUT HAS1 -1.2333508 3.80E-08 3.68E-07 PUT LINC00261 1.83243418 4.04E-08 3.88E-07 PUT SAP25 1.78258016 4.13E-08 3.95E-07 PUT LOC101927770 1.14051611 4.32E-08 4.10E-07 PUT LINC00540 1.28837241 4.24E-08 4.03E-07 PUT SGO1 1.18545315 3.84E-08 3.71E-07 PUT PLK2 -1.3933385 4.18E-08 3.99E-07 PUT KIF14 1.02659847 4.21E-08 4.02E-07 PUTCCNA1 -1.393222 4.89E-08 4.55E-07 PUT CGREF1 -1.0856493 4.23E-08 4.03E-07 PUT DSG1 -1.6393647 2.51E-08 2.62E-07 PUT SV2A -1.0923057 4.55E-08 4.29E-07 PUT MT1G 1.63670634 4.43E-08 4.18E-07 PUT LINC02664 1.08844554 5.16E-08 4.75E-07 PUT TMEM200B -1.3516026 5.13E-08 4.73E-07 PUT CDKN1A 1.32964027 4.59E-08 4.32E-07 PUT DCAF4L1 1.00667831 5.18E-08 4.76E-07 PUT KRT26 1.61086142 5.30E-08 4.86E-07 PUT C1orf94 -1.8662182 3.07E-08 3.08E-07 PUT CACNB1 -1.0621298 4.64E-08 4.36E-07 PUT CCNA2 1.00812084 5.40E-08 4.93E-07 PUT FAM83A 1.00700617 4.51E-08 4.26E-07 PUT CNPY1 -1.5404804 2.97E-08 3.00E-07 PUT AMPH -1.0097812 4.89E-08 4.55E-07 PUT CDA 1.50824202 5.13E-08 4.73E-07 PUT IGFN1 -1.6605761 5.66E-08 5.13E-07 PUT CAMKK2 -1.0641765 5.07E-08 4.69E-07 PUT KRT5 -1.5229386 4.82E-08 4.50E-07 PUT PPP3R1 -1.1278758 5.23E-08 4.79E-07 PUT SYTL5 -1.482509 5.35E-08 4.89E-07 PUT ACTN2 -1.3792333 5.06E-08 4.68E-07 PUT LSMEM1 1.0091031 5.73E-08 5.17E-07 PUT LMO1 -1.1500503 5.08E-08 4.69E-07 PUT KIRREL2 -1.1598225 5.96E-08 5.36E-07 PUT RHOV -1.7064296 4.16E-08 3.97E-07 PUT STARD5 -1.3842727 5.90E-08 5.31E-07 PUT PABPC1L2B -1.3837998 6.36E-08 5.65E-07 PUT PKP1 -1.4306366 5.69E-08 5.14E-07 PUT ADAMTS9- 1.90722318 5.36E-08 4.90E-07 PUT AS1 SNAP91 -1.1103733 5.50E-08 5.01E-07 PUT LOC100505795 1.64645727 4.86E-08 4.53E-07 PUT UCHL1 -1.1641126 5.96E-08 5.36E-07 PUT LOC100128006 1.02835576 5.43E-08 4.96E-07 PUT RNY4 1.22101548 6.95E-08 6.07E-07 PUT CKMT1A -1.5584639 6.12E-08 5.48E-07 PUT DACH2 -1.318522 6.84E-08 6.01E-07 PUT NAPB -1.0247375 6.37E-08 5.65E-07 PUT SLC52A3 1.39670619 7.54E-08 6.49E-07 PUT BPESC1 1.53749593 4.87E-08 4.54E-07 PUT SLC35D3 -1.8495325 7.71E-08 6.61E-07 PUTTMEM184A 1.09647489 6.87E-08 6.02E-07 PUT RHOXF2B 1.23883044 7.54E-08 6.49E-07 PUT BCL3 1.17807792 7.82E-08 6.69E-07 PUT SRGAP3-AS3 1.4218934 5.28E-08 4.84E-07 PUT ULK4P1 -1.2198866 7.09E-08 6.18E-07 PUT MIR3945HG 1.46922059 7.02E-08 6.12E-07 PUT CX3CR1 -1.5362414 7.45E-08 6.43E-07 PUT LINC01127 1.33966491 6.84E-08 6.01E-07 PUT MIR8066 2.00596318 5.49E-08 5.01E-07 PUT COL6A5 -1.8303477 4.96E-08 4.60E-07 PUT PDE2A -1.1822766 7.44E-08 6.42E-07 PUT MARCHF4 -1.3740146 7.92E-08 6.75E-07 PUT HPDL -1.0625279 8.51E-08 7.17E-07 PUT SCN4B -1.9122394 7.87E-08 6.71E-07 PUT DKK2 -1.429045 6.81E-08 5.99E-07 PUT GFRAL 1.68239067 4.57E-08 4.30E-07 PUT LINC00477 1.32683584 7.07E-08 6.16E-07 PUT TMEM132D -1.1318835 9.02E-08 7.53E-07 PUT SVOP -1.5397907 8.44E-08 7.12E-07 PUT HS3ST5 -1.0256443 8.90E-08 7.45E-07 PUT LUCAT1 1.24293068 9.27E-08 7.70E-07 PUT FLJ42393 1.2050197 9.72E-08 7.99E-07 PUT HTR5A -1.682471 1.04E-07 8.44E-07 PUT SYT2 -1.7820049 8.90E-08 7.45E-07 PUT RNY3 1.19561705 9.24E-08 7.67E-07 PUT GOLGA8G -1.8807547 1.05E-07 8.51E-07 PUT CXADRP3 1.39229066 8.63E-08 7.25E-07 PUT LOC100506551 -1.0553218 1.09E-07 8.79E-07 PUT RSPO4 -1.1507516 1.06E-07 8.55E-07 PUT FGF8 1.10973987 1.07E-07 8.60E-07 PUT PLEK -1.0139532 1.07E-07 8.60E-07 PUT LCA10 1.12482139 1.02E-07 8.33E-07 PUT OBSCN-AS1 -1.4062608 1.02E-07 8.35E-07 PUT CALY -1.4177396 9.76E-08 8.02E-07 PUT TMOD1 -1.1098804 9.73E-08 7.99E-07 PUT COL26A1 -1.1617099 1.14E-07 9.10E-07 PUT HYAL4 1.13921949 1.03E-07 8.37E-07 PUT RNF175 -1.0709781 1.09E-07 8.79E-07 PUT LOC284933 1.85823067 1.03E-07 8.36E-07 PUT CRABP1 -1.276163 1.06E-07 8.55E-07 PUT VIT -1.4697655 8.99E-08 7.51E-07 PUT SYT13 -1.4248445 1.12E-07 8.95E-07 PUTCFAP61 -1.0722053 1.27E-07 9.95E-07 PUT BIRC5 1.03179023 1.21E-07 9.58E-07 PUT LOC105369509 1.40344805 1.03E-07 8.38E-07 PUT CPNE4 -1.3843988 1.24E-07 9.76E-07 PUT PPP1R1B -1.0367658 1.28E-07 1.00E-06 PUT TNIP3 1.10249414 1.25E-07 9.87E-07 PUT NXF2B -1.4875533 9.80E-08 8.04E-07 PUT VAT1L -1.8378472 1.16E-07 9.24E-07 PUT DNAJB1 1.760481 1.19E-07 9.43E-07 PUT GPR158 -1.3983627 1.21E-07 9.55E-07 PUT SLC14A1 1.30302893 1.21E-07 9.58E-07 PUT NELL2 -1.3721005 1.26E-07 9.89E-07 PUT HAS2 1.01027524 1.54E-07 1.17E-06 PUT RHOD 1.17639283 1.48E-07 1.14E-06 PUT C8orf49 1.1233924 1.58E-07 1.20E-06 PUT GOLGA8H -1.6506575 1.47E-07 1.13E-06 PUT MT1A 1.31480034 1.59E-07 1.21E-06 PUT TNFRSF8 -1.946709 1.69E-07 1.28E-06 PUT PABPC1L2A -1.141793 1.69E-07 1.28E-06 PUT ANKRD20A2 1.25060367 1.43E-07 1.10E-06 PUT CHRNA7 -1.0051777 1.74E-07 1.30E-06 PUT GRIK1-AS1 1.11307523 1.41E-07 1.09E-06 PUT SFTPA2 -1.6333248 1.06E-07 8.55E-07 PUT GUCY1B1 -1.0833445 1.50E-07 1.15E-06 PUT CBLN1 -1.1971469 1.85E-07 1.37E-06 PUT MT1X 1.20273898 1.52E-07 1.16E-06 PUT NNMT 1.20549864 1.70E-07 1.28E-06 PUT ACR -1.1805545 1.70E-07 1.28E-06 PUT CRNDE -1.0440569 1.92E-07 1.42E-06 PUT ANKRD34A -1.1133871 1.66E-07 1.26E-06 PUT EFNA3 -1.0757959 1.70E-07 1.28E-06 PUT PLPPR5 -1.0846839 1.91E-07 1.41E-06 PUT KIF18A 1.06880248 1.88E-07 1.39E-06 PUT PEG10 -1.1808126 1.77E-07 1.32E-06 PUT CHGB -1.3127976 1.72E-07 1.29E-06 PUT LRRC14B -1.7603163 1.27E-07 9.97E-07 PUT VSIG8 1.45473481 1.94E-07 1.43E-06 PUT CALB1 -1.68498 1.80E-07 1.34E-06 PUT MIR519A2 1.29743831 2.20E-07 1.59E-06 PUT STAT4 -1.2567366 2.18E-07 1.58E-06 PUT RET -1.007608 2.22E-07 1.60E-06 PUT MYLK2 -1.5219898 2.04E-07 1.50E-06 PUTINPP5A -1.0637349 1.88E-07 1.40E-06 PUT MTHFD2 1.06553365 2.06E-07 1.51E-06 PUT CAMKK1 -1.320555 1.91E-07 1.42E-06 PUT LOC100287042 -1.0335012 2.37E-07 1.69E-06 PUT USP46-AS1 -1.1906349 2.18E-07 1.58E-06 PUT GPRIN2 -1.6922969 1.77E-07 1.33E-06 PUT LINC02214 1.58440477 1.49E-07 1.14E-06 PUT LINC01730 1.19991335 2.18E-07 1.58E-06 PUT RBP3 -1.1557071 2.05E-07 1.51E-06 PUT KIF12 -1.5372591 2.49E-07 1.77E-06 PUT HIGD1C 1.61764415 1.22E-07 9.65E-07 PUT TESC -1.1451678 2.09E-07 1.53E-06 PUT GABRD -1.5299161 2.10E-07 1.54E-06 PUT FKBP5 1.21116872 2.11E-07 1.54E-06 PUT EPHA5 -1.2205727 2.69E-07 1.89E-06 PUT AMY2A -1.5776793 2.32E-07 1.66E-06 PUT TMEFF1 -1.2142061 2.63E-07 1.85E-06 PUT CCNB3 -1.2366473 2.37E-07 1.69E-06 PUT GAD1 -1.6282203 2.30E-07 1.65E-06 PUT STUM -1.0834187 2.34E-07 1.68E-06 PUT KCNE5 -1.1189204 2.86E-07 1.98E-06 PUT CACNA2D3 -1.157419 2.37E-07 1.69E-06 PUT ARHGAP44 -1.0430254 2.33E-07 1.67E-06 PUT REM2 -1.3942961 3.02E-07 2.08E-06 PUT SLC12A5 -1.5552299 2.53E-07 1.79E-06 PUT SALRNA2 1.43564084 2.13E-07 1.55E-06 PUT LOC100287944 -1.5066596 1.97E-07 1.45E-06 PUT DACT2 -1.3861537 2.64E-07 1.86E-06 PUT TGFB3 1.24167352 2.62E-07 1.84E-06 PUT GACAT2 -1.7071527 2.02E-07 1.49E-06 PUT EFNB3 -1.23052 2.70E-07 1.89E-06 PUT NGEF -1.7388698 2.83E-07 1.97E-06 PUT STRIP2 -1.4900604 2.73E-07 1.91E-06 PUT CPNE7 -1.0383409 3.22E-07 2.20E-06 PUT SMIM18 -1.1038061 3.20E-07 2.20E-06 PUT FRAS1 -1.025748 3.03E-07 2.09E-06 PUT SYT6 -1.087415 3.19E-07 2.19E-06 PUT OR1F1 -1.7863854 2.52E-07 1.79E-06 PUT PMEL 1.47385327 1.97E-07 1.45E-06 PUT CRYBA1 1.62062713 1.89E-07 1.40E-06 PUT S100A4 1.1562586 3.69E-07 2.48E-06 PUT MISP 1.17400173 3.08E-07 2.12E-06 PUTPKN3 1.00523287 3.73E-07 2.50E-06 PUT TNNI1 1.16996984 2.73E-07 1.91E-06 PUT STX1B -1.2134245 3.30E-07 2.25E-06 PUT NRIP3 -1.0647593 3.20E-07 2.19E-06 PUT NMNAT2 -1.3566521 3.21E-07 2.20E-06 PUT GPR158-AS1 -1.3185764 3.83E-07 2.56E-06 PUT PRMT8 -1.3870916 3.32E-07 2.26E-06 PUT SH2D5 -1.4598958 3.34E-07 2.27E-06 PUT PRLHR -1.0943583 4.19E-07 2.75E-06 PUT LINC00460 -1.5539487 4.22E-07 2.77E-06 PUT BLID 1.50817796 2.42E-07 1.72E-06 PUT PNLIPRP1 1.07761948 3.99E-07 2.65E-06 PUT SEC14L3 1.0761592 4.16E-07 2.74E-06 PUT MIR5690 2.03227899 2.14E-07 1.56E-06 PUT GBX2 -1.1901213 4.32E-07 2.82E-06 PUT ATP11A-AS1 1.0892159 4.28E-07 2.80E-06 PUT ARC -1.0521681 3.94E-07 2.62E-06 PUT LEF1-AS1 1.06244682 3.89E-07 2.59E-06 PUT ATP2B2 -1.1041615 3.74E-07 2.51E-06 PUT GOLT1A -1.3627773 4.41E-07 2.87E-06 PUT TMEM150B 1.20867768 4.05E-07 2.68E-06 PUT LL22NC01- 1.39801834 4.22E-07 2.77E-06 PUT 81G9.3 SULT4A1 -1.5265304 3.79E-07 2.53E-06 PUT MAGEE2 -1.0896338 4.67E-07 3.00E-06 PUT PARM1 -1.2422251 3.88E-07 2.58E-06 PUT ABCC5-AS1 1.54368258 3.73E-07 2.51E-06 PUT CDK5R2 -1.4991405 3.94E-07 2.62E-06 PUT WDR88 -1.0711064 4.75E-07 3.05E-06 PUT TMEM92 1.00599179 4.36E-07 2.84E-06 PUT ADAM23 -1.1326346 4.06E-07 2.69E-06 PUT CAP2 -1.2506984 4.07E-07 2.69E-06 PUT CA4 -1.1646262 5.12E-07 3.24E-06 PUT RASGRP1 -1.180809 4.24E-07 2.78E-06 PUT KCNQ3 -1.2326531 4.16E-07 2.74E-06 PUT MIOX 1.18141011 4.06E-07 2.69E-06 PUT SEZ6 -1.4411881 4.22E-07 2.77E-06 PUT LHFPL4 -1.000377 4.20E-07 2.76E-06 PUT PTPRR -1.185022 5.05E-07 3.21E-06 PUT DGKB -1.3851686 4.26E-07 2.79E-06 PUT NAV2-AS4 1.27704105 3.62E-07 2.44E-06 PUT SYTL4 1.04463783 4.37E-07 2.85E-06 PUT SULT2A1 1.06007894 4.88E-07 3.12E-06 PUTPLA1A 1.56897738 5.42E-07 3.42E-06 PUT SNAP25 -1.6119234 4.82E-07 3.09E-06 PUT UNC5A -1.2809336 4.49E-07 2.91E-06 PUT LINC01013 1.06897708 4.47E-07 2.90E-06 PUT PDK4 1.00297313 4.42E-07 2.87E-06 PUT LOC101929420 1.27082572 4.65E-07 3.00E-06 PUT HMOX1 1.04367902 4.86E-07 3.11E-06 PUT DMRT1 1.29654341 4.09E-07 2.70E-06 PUT SERPINF2 1.07900254 5.83E-07 3.63E-06 PUT SLC22A14 1.20641791 5.09E-07 3.23E-06 PUT LOC286177 1.15221373 4.63E-07 2.99E-06 PUT CNR1 -1.6772826 4.83E-07 3.09E-06 PUT RIMBP2 -1.189653 5.10E-07 3.24E-06 PUT DDC -1.4114007 5.86E-07 3.64E-06 PUT SUSD4 -1.1494059 4.89E-07 3.12E-06 PUT SIX4 1.14104905 6.20E-07 3.82E-06 PUT KRTAP5-7 -1.2535271 4.37E-07 2.85E-06 PUT CYP4B1 1.44426011 5.61E-07 3.52E-06 PUT ENC1 -1.6847418 5.18E-07 3.28E-06 PUT LRIT2 -1.3627633 6.50E-07 3.98E-06 PUT RBP4 -1.2221548 5.56E-07 3.49E-06 PUT CIDEA -1.6177149 6.74E-07 4.11E-06 PUT C11orf87 -1.3648627 5.88E-07 3.65E-06 PUT TUSC7 1.18862431 7.23E-07 4.35E-06 PUT LINC00824 1.10182235 7.12E-07 4.30E-06 PUT INSM2 -1.1729191 7.26E-07 4.37E-06 PUT TMEM196 -1.1634554 7.18E-07 4.33E-06 PUT SNORA77 2.23097513 2.97E-07 2.05E-06 PUT SFN -1.1033715 7.54E-07 4.52E-06 PUT LOC100128770 1.04020445 6.61E-07 4.05E-06 PUT CACNA1C- 1.5441055 5.68E-07 3.56E-06 PUT AS4 KIF1C 1.00613959 6.97E-07 4.23E-06 PUT NOXO1 -1.5018554 5.84E-07 3.63E-06 PUT RAB3C -1.5401983 6.41E-07 3.94E-06 PUT FBXL16 -1.4713607 7.35E-07 4.42E-06 PUT SLC22A9 1.0482648 8.00E-07 4.75E-06 PUT CLEC12A 1.14642873 6.85E-07 4.17E-06 PUT APOBEC3A 1.27968162 6.12E-07 3.79E-06 PUT TMEM171 -1.5090847 8.00E-07 4.75E-06 PUT CKMT1B -1.2831605 6.96E-07 4.23E-06 PUT PDE10A -1.5404232 7.09E-07 4.29E-06 PUT SPRY4-IT1 1.2654339 7.21E-07 4.35E-06 PUTTEAD4 1.12951724 9.10E-07 5.29E-06 PUT LINC02210- -2.2973796 7.22E-07 4.35E-06 PUT CRHR1 KNCN -1.6107336 7.06E-07 4.28E-06 PUT PTGES3L- -2.2061537 8.73E-07 5.11E-06 PUT AARSD1 C1orf210 1.17952609 7.99E-07 4.74E-06 PUT MMP13 1.2507926 6.70E-07 4.09E-06 PUT FBXO43 1.18426688 8.88E-07 5.19E-06 PUT ABLIM2 -1.0006437 7.96E-07 4.73E-06 PUT NUDT11 -1.1797215 8.83E-07 5.16E-06 PUT SPTBN2 -1.1873386 8.49E-07 5.00E-06 PUT NCEH1 -1.1233221 8.18E-07 4.84E-06 PUT IGFBPL1 -1.4714706 1.00E-06 5.74E-06 PUT ACRV1 -1.193427 1.01E-06 5.80E-06 PUT CALB2 -1.2429852 8.80E-07 5.14E-06 PUT ACHE -1.2514422 8.25E-07 4.87E-06 PUT NUCB1-AS1 2.02852489 6.07E-07 3.76E-06 PUT HNF1B 1.14141795 9.96E-07 5.72E-06 PUT CNTNAP2- 1.08269692 1.01E-06 5.77E-06 PUT AS1 SV2B -1.193733 8.78E-07 5.14E-06 PUT PCAT29 1.24949443 8.72E-07 5.11E-06 PUT NECAB2 -1.0938444 8.96E-07 5.22E-06 PUT TRH -1.6178458 1.12E-06 6.32E-06 PUT OR51B5 1.0634216 1.03E-06 5.88E-06 PUT PDZD4 -1.0001238 1.01E-06 5.80E-06 PUT PDLIM1 1.33894553 1.18E-06 6.62E-06 PUT GPR55 -1.5428465 1.22E-06 6.79E-06 PUT RGS14 -1.749755 1.01E-06 5.78E-06 PUT PTHLH -1.1494167 1.25E-06 6.94E-06 PUT TSPAN13 -1.0586284 9.77E-07 5.63E-06 PUT CDHR1 -1.2780439 9.80E-07 5.64E-06 PUT TDRD5 -1.3300458 1.28E-06 7.09E-06 PUT LINC01840 1.09378046 1.19E-06 6.64E-06 PUT SEMA3G -1.1544196 1.09E-06 6.16E-06 PUT LINC02192 -1.3711592 1.26E-06 7.01E-06 PUT SGK2 -1.0339953 1.17E-06 6.56E-06 PUT ZIM3 1.18481878 1.15E-06 6.48E-06 PUT UPK1A-AS1 1.07509879 1.30E-06 7.17E-06 PUT ADGRF2 1.10774366 1.27E-06 7.06E-06 PUT MUC5B -1.6583255 1.26E-06 7.01E-06 PUT GFI1B 1.18348581 1.18E-06 6.63E-06 PUT NTRK3-AS1 1.75110709 8.17E-07 4.84E-06 PUTLINC01441 1.45002093 9.24E-07 5.36E-06 PUT PDE1B -1.6279845 1.24E-06 6.91E-06 PUT GABRE 1.17623408 1.50E-06 8.10E-06 PUT LBX2 1.52851341 1.03E-06 5.88E-06 PUT PCP4 -1.2949357 1.30E-06 7.16E-06 PUT GALNT17 -1.1143199 1.20E-06 6.71E-06 PUT ZNF664- -1.185857 1.69E-06 8.98E-06 PUT RFLNA EIF4EBP1 1.0165311 1.66E-06 8.87E-06 PUT IL4R 1.16261593 1.41E-06 7.69E-06 PUT LINC02525 -1.0108384 1.70E-06 9.03E-06 PUT DOCK9-AS1 1.43888595 1.14E-06 6.42E-06 PUT PITX1 1.06273398 1.77E-06 9.36E-06 PUT ST8SIA6-AS1 1.07982742 1.76E-06 9.29E-06 PUT SYT8 1.90229818 1.13E-06 6.35E-06 PUT ZNF385B -1.1480235 1.50E-06 8.13E-06 PUT UNC13A -1.2064728 1.48E-06 8.05E-06 PUT LRTM2 -1.5853977 1.49E-06 8.06E-06 PUT EPHA8 -1.165319 1.88E-06 9.82E-06 PUT KCNS2 -1.4867685 1.90E-06 9.94E-06 PUT HAR1A -1.0808726 1.83E-06 9.61E-06 PUT SLC2A13 -1.0707394 1.49E-06 8.09E-06 PUT PCSK2 -1.2328776 1.50E-06 8.12E-06 PUT RPH3A -1.2332968 1.52E-06 8.20E-06 PUT LNX1 -1.1470864 1.62E-06 8.66E-06 PUT FRMD6-AS1 1.00649501 2.02E-06 1.05E-05 PUT FMOD -1.060159 2.07E-06 1.07E-05 PUT ELAVL2 -1.0193865 1.82E-06 9.59E-06 PUT LINC01363 1.0446751 1.86E-06 9.73E-06 PUT IQGAP3 1.08631224 2.03E-06 1.05E-05 PUT TMEM121B -1.178293 1.79E-06 9.43E-06 PUT CHRNB2 -1.4079897 1.75E-06 9.26E-06 PUT GREM2 -1.0344411 2.04E-06 1.05E-05 PUT VSTM2L -1.1127778 1.78E-06 9.40E-06 PUT THOC7-AS1 1.13816198 1.72E-06 9.13E-06 PUT NRGN -1.4478441 2.01E-06 1.04E-05 PUT SLC32A1 -1.686548 1.82E-06 9.57E-06 PUT PDGFD -1.135302 2.42E-06 1.22E-05 PUT ACTL6B -1.2285468 1.90E-06 9.91E-06 PUT HGFAC 1.4246927 2.38E-06 1.20E-05 PUT GPR139 -2.0646948 2.10E-06 1.08E-05 PUT IL6 2.07786752 1.79E-06 9.43E-06 PUT WT1 -1.5930765 2.35E-06 1.19E-05 PUTNCDN -1.406054 2.27E-06 1.15E-05 PUT ARPP21 -1.4227219 2.21E-06 1.13E-05 PUT LINC01676 1.22041231 1.94E-06 1.01E-05 PUT KCNK9 -1.4350438 2.60E-06 1.30E-05 PUT NKX1-2 -1.0712519 2.25E-06 1.15E-05 PUT SLITRK3 -1.0372548 2.21E-06 1.13E-05 PUT LYPD4 1.21892694 2.00E-06 1.04E-05 PUT ICAM5 -1.5978484 2.14E-06 1.10E-05 PUT LOC101929353 -1.760099 2.41E-06 1.22E-05 PUT SH3GL2 -1.2390576 2.12E-06 1.09E-05 PUT CXCL1 1.69707714 2.62E-06 1.31E-05 PUT LOC102723831 1.50235689 2.01E-06 1.04E-05 PUT KLHL10 -1.3038876 2.11E-06 1.09E-05 PUT NSG2 -1.4900751 2.34E-06 1.19E-05 PUT PCP4L1 -1.6733706 2.20E-06 1.12E-05 PUT FSTL4 -1.2766079 2.40E-06 1.21E-05 PUT P4HA2 1.02529117 2.48E-06 1.25E-05 PUT CACNG1 -1.433164 2.77E-06 1.37E-05 PUT RGS4 -1.2747046 2.23E-06 1.14E-05 PUT EEF1A2 -1.2903812 2.38E-06 1.20E-05 PUT SMPD3 -1.1371236 2.24E-06 1.14E-05 PUT C6orf141 -1.7061529 2.84E-06 1.40E-05 PUT HSPA1A 1.77743312 2.54E-06 1.27E-05 PUT TPBG -1.2995629 2.37E-06 1.20E-05 PUT ADH1B 1.16307573 3.12E-06 1.51E-05 PUT SLC16A12 1.00431619 3.16E-06 1.53E-05 PUT GUCA1A -1.1069352 3.09E-06 1.50E-05 PUT GLS2 -1.1977189 2.66E-06 1.32E-05 PUT FGF18 1.03647076 3.07E-06 1.49E-05 PUT CD81-AS1 -1.1219967 2.78E-06 1.37E-05 PUT HIPK4 -1.5383989 2.72E-06 1.35E-05 PUT LINC00242 -1.1686847 3.38E-06 1.61E-05 PUT PHKA1-AS1 1.03871318 3.00E-06 1.47E-05 PUT VSTM5 -1.3039573 3.36E-06 1.61E-05 PUT SMIM32 -1.6025348 3.44E-06 1.64E-05 PUT HSPA1B 1.6418131 2.84E-06 1.40E-05 PUT SYT5 -1.1525809 2.68E-06 1.33E-05 PUT PHEX-AS1 -1.0489778 3.34E-06 1.60E-05 PUT LOC285847 1.16129689 3.18E-06 1.53E-05 PUT COMP 1.05146371 3.44E-06 1.64E-05 PUT SLC6A17 -1.2195525 2.70E-06 1.34E-05 PUT ACY3 -1.4766892 3.62E-06 1.71E-05 PUTADAMTS3 -1.1463547 3.37E-06 1.61E-05 PUT HSP90AA1 1.02935115 3.41E-06 1.63E-05 PUT SYT4 -1.3817057 2.90E-06 1.42E-05 PUT NMUR2 1.58411697 3.87E-06 1.81E-05 PUT MRAP2 -1.0005396 3.43E-06 1.64E-05 PUT KIAA1549L -1.0734968 2.93E-06 1.44E-05 PUT FLJ46284 1.513421 2.98E-06 1.46E-05 PUT PSPN 1.23085099 3.36E-06 1.61E-05 PUT ATP6V1B1- 1.11701857 3.78E-06 1.78E-05 PUT AS1 MACROD2- 1.50747478 3.41E-06 1.63E-05 PUT IT1 SH2D7 1.07721137 4.12E-06 1.92E-05 PUT LINC02393 1.30325084 3.69E-06 1.74E-05 PUT PAPPA-AS1 2.48468546 3.06E-06 1.49E-05 PUT HTR1E -1.3350533 4.48E-06 2.07E-05 PUT CPLX2 -1.3596852 3.84E-06 1.80E-05 PUT SCRT1 -1.0595278 3.40E-06 1.63E-05 PUT ENTPD3 -1.4959058 3.52E-06 1.67E-05 PUT GLDN -1.0280581 3.42E-06 1.63E-05 PUT LOC100129620 -1.2123487 3.70E-06 1.74E-05 PUT UPK1A 1.66213892 3.33E-06 1.60E-05 PUT SNX31 1.50267784 4.64E-06 2.13E-05 PUT ATP1A3 -1.5043845 4.15E-06 1.93E-05 PUT ADCY10 1.07871569 5.05E-06 2.29E-05 PUT PNCK -1.0588067 3.97E-06 1.85E-05 PUT INHA -1.0601271 5.36E-06 2.40E-05 PUT CHRNA3 -1.1947739 5.35E-06 2.40E-05 PUT CARNS1 -1.2355738 4.22E-06 1.96E-05 PUT HTR2C -1.6075889 4.19E-06 1.95E-05 PUT KDF1 2.03206011 4.13E-06 1.92E-05 PUT KCNH1 -1.044341 4.62E-06 2.12E-05 PUT PTPRN -1.2925251 4.44E-06 2.05E-05 PUT EGR4 -1.4855845 5.19E-06 2.34E-05 PUT CACNA2D4 -1.0555415 6.09E-06 2.69E-05 PUT LOC100130264 1.12879636 5.16E-06 2.33E-05 PUT AOC1 1.29404445 4.59E-06 2.11E-05 PUT BBOX1-AS1 1.01500179 5.11E-06 2.31E-05 PUT MAGI2-AS2 1.80250844 4.12E-06 1.92E-05 PUT SPINK8 1.00995212 4.98E-06 2.26E-05 PUT NFE2 1.21156418 5.62E-06 2.51E-05 PUT LINC01616 -1.2706783 5.84E-06 2.59E-05 PUT SPDEF -1.1078598 5.87E-06 2.60E-05 PUT CHRM4 -1.8111623 5.62E-06 2.51E-05 PUTTXK 1.12829705 6.14E-06 2.71E-05 PUT PAX7 -1.4475222 6.18E-06 2.73E-05 PUT LOC100129603 1.74773788 5.05E-06 2.29E-05 PUT FLJ37201 1.3264409 4.78E-06 2.18E-05 PUT HES2 1.01792578 6.43E-06 2.82E-05 PUT HILPDA 1.06508729 5.55E-06 2.48E-05 PUT SNCB -1.0573595 5.35E-06 2.40E-05 PUT CPLX1 -1.0505547 5.63E-06 2.51E-05 PUT LINC00484 1.34784934 5.42E-06 2.43E-05 PUT ACPP 1.1390641 7.48E-06 3.21E-05 PUT L1CAM -1.4023708 5.53E-06 2.47E-05 PUT STAB2 1.12646009 6.66E-06 2.91E-05 PUT MYADML2 -1.0132325 7.05E-06 3.05E-05 PUT RGS9 -1.2190905 5.56E-06 2.48E-05 PUT WNT1 -1.6168081 7.48E-06 3.21E-05 PUT RTL9 -1.251982 7.75E-06 3.31E-05 PUT GPRIN3 -1.0478494 5.71E-06 2.54E-05 PUT LOC286178 1.20826262 7.07E-06 3.06E-05 PUT SLC11A1 1.00308964 6.48E-06 2.84E-05 PUT TMEM239 1.1365672 8.04E-06 3.42E-05 PUT LINC01993 1.04716661 8.77E-06 3.69E-05 PUT HPGD -1.0850227 8.67E-06 3.65E-05 PUT MT1H 1.59975823 8.14E-06 3.46E-05 PUT EGFL6 -1.4932537 6.88E-06 2.98E-05 PUT RGS8 -1.5007728 6.69E-06 2.92E-05 PUT WSCD2 -1.2626694 6.83E-06 2.96E-05 PUT LOC101928663 1.42824995 7.18E-06 3.10E-05 PUT PAK6 -1.1288077 7.04E-06 3.05E-05 PUT DLGAP2 -1.1469199 7.36E-06 3.17E-05 PUT PHACTR2-AS1 1.16710717 8.07E-06 3.43E-05 PUT C10orf105 1.27120089 7.46E-06 3.21E-05 PUT STK26 -1.1077273 9.59E-06 4.00E-05 PUT MTRNR2L1 1.2096468 9.84E-06 4.09E-05 PUT LOC101929613 1.22077491 9.10E-06 3.81E-05 PUT RAB27B -1.2214639 1.00E-05 4.15E-05 PUT RNU4ATAC 1.24920672 8.76E-06 3.69E-05 PUT CAMKV -1.3798937 7.95E-06 3.39E-05 PUT KRT86 -1.1110112 9.78E-06 4.06E-05 PUT KCNG3 -1.2614872 1.07E-05 4.40E-05 PUT LOC100506071 -1.5898046 1.08E-05 4.42E-05 PUT TNFRSF6B 3.66915316 1.08E-05 4.42E-05 PUT LINC00159 1.19170045 8.60E-06 3.63E-05 PUTDNAH3 1.10027495 1.02E-05 4.22E-05 PUT CNTN5 -1.0896051 1.13E-05 4.62E-05 PUT TMIE 1.27169718 1.08E-05 4.44E-05 PUT CXCR2 1.05472089 1.18E-05 4.78E-05 PUT MTRNR2L7 1.05070004 1.16E-05 4.70E-05 PUT LINC00692 1.11067705 9.98E-06 4.14E-05 PUT DNAH12 1.0924052 1.16E-05 4.71E-05 PUT OCA2 -1.2918459 1.24E-05 4.99E-05 PUT CHRM1 -1.4323316 9.06E-06 3.80E-05 PUT CARNMT1- 1.11667069 1.26E-05 5.06E-05 PUT AS1 LAMP5 -1.4950028 9.24E-06 3.86E-05 PUT PIANP -1.2145974 9.43E-06 3.94E-05 PUT ST8SIA2 -1.3581735 1.32E-05 5.29E-05 PUT LOC105373021 -1.1256735 1.29E-05 5.15E-05 PUT LEXM -1.2584583 1.26E-05 5.05E-05 PUT KCNB2 -1.0630625 1.37E-05 5.45E-05 PUT LINC00901 1.19168994 1.23E-05 4.96E-05 PUT TUBB1 1.0316452 1.20E-05 4.85E-05 PUT EGR3 -1.216502 1.00E-05 4.14E-05 PUT GRM5 -1.0312025 9.88E-06 4.10E-05 PUT TM4SF1 1.0199642 1.02E-05 4.23E-05 PUT CACNG3 -1.3772317 1.01E-05 4.19E-05 PUT HPCA -1.5134073 1.14E-05 4.65E-05 PUT LINC01596 1.02684285 1.37E-05 5.44E-05 PUT POU4F1 1.22408319 1.28E-05 5.14E-05 PUT C16orf90 1.6027441 1.05E-05 4.34E-05 PUT KCNAB2 -1.0172874 1.08E-05 4.44E-05 PUT RASD2 -1.4488649 1.11E-05 4.56E-05 PUT CPLX3 -1.0307866 1.36E-05 5.40E-05 PUT TRDN 1.15256398 1.42E-05 5.63E-05 PUT MTRNR2L10 1.10842942 1.15E-05 4.68E-05 PUT CACNA1H -1.1430396 1.08E-05 4.42E-05 PUT RAP1GAP -1.1625991 1.18E-05 4.78E-05 PUT ST8SIA3 -1.4793347 1.14E-05 4.65E-05 PUT RNY1 1.14190146 1.14E-05 4.66E-05 PUT SNORD63 1.40593394 1.34E-05 5.34E-05 PUT OR2W3 -1.3438038 1.47E-05 5.77E-05 PUT C6orf118 1.17640689 1.59E-05 6.21E-05 PUT GABRG2 -1.2431989 1.16E-05 4.70E-05 PUT STAC -1.0121913 1.62E-05 6.33E-05 PUT MYBPH 1.14790268 1.62E-05 6.32E-05 PUT NMRK2 1.79259455 1.25E-05 5.02E-05 PUTGJA3 -1.4915006 1.56E-05 6.10E-05 PUT ALOX12B -1.0214899 1.63E-05 6.35E-05 PUT CCDC87 -1.0324393 1.58E-05 6.17E-05 PUT MIR144 1.06981994 1.64E-05 6.37E-05 PUT ANKRD63 -1.6937802 1.70E-05 6.55E-05 PUT GOLGA8T -2.1687607 1.63E-05 6.35E-05 PUT TMEM130 -1.0812543 1.26E-05 5.07E-05 PUT CCKBR -1.2538922 1.64E-05 6.37E-05 PUT MPZL2 1.14475368 1.72E-05 6.64E-05 PUT LTB4R2 -1.0181966 1.72E-05 6.64E-05 PUT PACSIN1 -1.2131664 1.41E-05 5.57E-05 PUT S100A8 2.05479026 1.86E-05 7.13E-05 PUT GABRB3 -1.0854958 1.34E-05 5.35E-05 PUT HEATR9 1.12195219 1.90E-05 7.23E-05 PUT SGCG -1.0724816 1.77E-05 6.80E-05 PUT GABRA3 -1.0344506 1.69E-05 6.55E-05 PUT RPE65 -1.8295333 1.82E-05 7.00E-05 PUT POTEH 2.01164612 1.91E-05 7.27E-05 PUT DSG3 1.29811705 1.67E-05 6.48E-05 PUT CBLN4 -1.5769518 2.01E-05 7.59E-05 PUT SLC8A2 -1.1294139 1.46E-05 5.74E-05 PUT LTA 1.45330151 1.66E-05 6.44E-05 PUT SYNGR3 -1.0836107 1.48E-05 5.81E-05 PUT PWAR1 1.03390089 2.08E-05 7.82E-05 PUT LINC00485 1.07778439 2.17E-05 8.12E-05 PUT TAC1 -1.6833435 1.56E-05 6.10E-05 PUT XKR7 -1.0553018 2.19E-05 8.17E-05 PUT SLC1A7 1.66816662 2.35E-05 8.70E-05 PUT MTRNR2L6 1.19199475 1.85E-05 7.09E-05 PUT GADD45G 1.06982815 2.01E-05 7.60E-05 PUT PRH1- -1.3937843 2.35E-05 8.70E-05 PUT TAS2R14 INA -1.2196038 1.65E-05 6.42E-05 PUT MAGEL2 -1.2591656 2.13E-05 7.96E-05 PUT MS4A14 1.21082854 2.39E-05 8.84E-05 PUT GABRA1 -1.0952678 1.77E-05 6.80E-05 PUT LOC101927139 1.13929354 2.46E-05 9.06E-05 PUT LOC100131635 1.53301263 2.05E-05 7.73E-05 PUT FAM189A1 -1.0117156 1.88E-05 7.17E-05 PUT ODF3L2 1.07677278 2.59E-05 9.48E-05 PUT KCNC2 -1.4952735 2.46E-05 9.07E-05 PUT LOC101928140 1.20044999 2.55E-05 9.35E-05 PUT COL25A1 -1.1983397 2.33E-05 8.64E-05 PUTGYS2 1.21701603 2.62E-05 9.56E-05 PUT LINC01679 1.29036035 2.59E-05 9.47E-05 PUT SHISAL1 -1.1042253 2.19E-05 8.18E-05 PUT PTPRT -1.0663613 2.16E-05 8.06E-05 PUT RNU12 1.15765628 3.12E-05 0.00011196 PUT FRG2C 1.19427058 3.16E-05 0.00011331 PUT RIMBP3C -1.6117864 3.18E-05 0.00011384 PUT FNDC1 -1.4299842 3.22E-05 0.00011512 PUT SP9 -1.2561397 3.07E-05 0.0001104 PUT ANO3 -1.6702531 2.40E-05 8.88E-05 PUT NCR1 1.11553667 3.07E-05 0.0001103 PUT KCNK4 -1.0210344 3.06E-05 0.0001102 PUT FAM155A-IT1 1.18748805 3.48E-05 0.00012286 PUT FOXF1 1.02071297 3.22E-05 0.00011517 PUT TRIML2 -1.2858143 3.18E-05 0.00011384 PUT DNAJB5-DT 1.45606216 2.88E-05 0.00010465 PUT ZSWIM8-AS1 1.11616063 3.60E-05 0.00012654 PUT CEACAM5 1.17834987 3.37E-05 0.00011973 PUT MIR320D1 1.2502655 3.23E-05 0.00011525 PUT GLRA4 -1.1729469 3.45E-05 0.00012186 PUT CRH -1.2148764 3.75E-05 0.0001313 PUT SNORA12 1.29270555 3.60E-05 0.0001266 PUT KCNIP2 -1.0555365 2.75E-05 0.00010018 PUT UNC5D -1.0295656 3.34E-05 0.00011883 PUT AGAP2 -1.1329867 2.91E-05 0.00010541 PUT AADACL3 1.01301541 3.43E-05 0.00012154 PUT NIBAN3 1.28834096 3.79E-05 0.00013237 PUT TEX101 1.13726251 3.99E-05 0.00013876 PUT CENPVL1 -1.143522 4.01E-05 0.00013925 PUT PCDH8 -1.3708923 3.06E-05 0.0001102 PUT ANKRD34C- -1.0004328 4.45E-05 0.00015209 PUT AS1 MCHR2 -1.2937925 4.25E-05 0.00014609 PUT EVPL -1.1938082 4.40E-05 0.00015093 PUT CACNA1S -1.0896298 4.55E-05 0.00015527 PUT DLGAP3 -1.0755239 3.11E-05 0.00011185 PUT C20orf173 1.25114995 4.00E-05 0.00013891 PUT S100A12 2.34229451 4.06E-05 0.00014072 PUT SCX 1.03343927 4.73E-05 0.00016062 PUT PLCXD2 -1.2163744 4.61E-05 0.00015708 PUT VSTM2A -1.1174816 3.43E-05 0.00012154 PUT TESPA1 -1.2925976 3.40E-05 0.0001205 PUT LOC101927950 1.19594313 5.17E-05 0.0001737 PUTC19orf33 1.02977083 5.22E-05 0.00017533 PUT DRD3 -1.6535917 5.33E-05 0.00017827 PUT ANGPTL4 1.01127961 3.56E-05 0.0001255 PUT ST6GALNAC5 -1.1596476 4.49E-05 0.00015345 PUT LIN28B-AS1 -1.0642536 5.32E-05 0.00017791 PUT SNORD115-45 -1.22782 5.43E-05 0.00018104 PUT CLTRN -1.0056411 5.75E-05 0.00019059 PUT LINC01570 1.03076521 5.33E-05 0.00017823 PUT GLI1 1.3764595 6.09E-05 0.00020068 PUT MIR3663HG 1.21511698 6.02E-05 0.00019877 PUT RN7SK 1.2464534 4.41E-05 0.00015104 PUT KCNQ5 -1.3116568 4.25E-05 0.00014624 PUT MTRNR2L4 1.15601781 4.59E-05 0.00015645 PUT FOXN4 1.39075895 5.27E-05 0.0001765 PUT FAM163A -1.1724926 6.60E-05 0.00021466 PUT SMAD1-AS2 1.48953209 5.99E-05 0.00019778 PUT PENK -1.9039455 4.93E-05 0.00016651 PUT CDHR5 -1.067164 6.53E-05 0.00021275 PUT AMN 1.06392266 6.85E-05 0.00022159 PUT LOC401442 -1.1611742 7.26E-05 0.00023334 PUT SCG2 -1.1863882 5.26E-05 0.0001763 PUT ATOH7 -1.0468378 7.65E-05 0.0002446 PUT TMEM238L 1.35154528 7.12E-05 0.0002292 PUT TUNAR -1.1601803 5.24E-05 0.00017588 PUT DSCAM-IT1 1.26542616 7.26E-05 0.00023334 PUT MMRN1 1.4384137 8.13E-05 0.00025811 PUT GOLGA8K -1.6761443 8.11E-05 0.00025761 PUT CHGA -1.0148629 5.53E-05 0.00018404 PUT LINC01123 -1.0929145 7.13E-05 0.00022945 PUT DNMT3L 1.45862905 7.69E-05 0.0002456 PUT TMPRSS11A 1.02768958 8.45E-05 0.0002669 PUT CKM 1.1615722 9.51E-05 0.00029615 PUT SPRNP1 -1.1215528 9.61E-05 0.00029877 PUT SPTB -1.0940311 6.61E-05 0.00021488 PUT ADAMTSL1 -1.0227746 0.00010255 0.00031673 PUT PAQR9 -1.1656308 0.00010245 0.00031652 PUT CUZD1 1.20613123 0.0001017 0.00031441 PUT CP 1.33938763 7.16E-05 0.00023032 PUT FAM237A -1.1862898 0.00010599 0.00032626 PUT C3orf86 1.07414365 9.89E-05 0.00030702 PUT MME -1.2710676 7.38E-05 0.00023691 PUT SYN2 -1.2429235 7.20E-05 0.00023149 PUTHTR3A -1.3557853 0.00010953 0.00033595 PUT RNA5S9 1.8981806 0.00011449 0.00034909 PUT CAMK4 -1.0901732 7.52E-05 0.00024108 PUT LOC101927447 1.00123619 0.00011216 0.00034283 PUT MTRNR2L8 1.03086112 0.00011458 0.00034924 PUT ETV2 1.03768592 0.00010945 0.00033588 PUT RNF216-IT1 1.20240247 0.0001152 0.00035058 PUT CRYGD -1.1718373 0.00011869 0.0003597 PUT CRYM -1.3446854 8.15E-05 0.00025877 PUT OLFM4 -1.1211321 0.00012809 0.00038519 PUT PDYN -1.7184185 8.77E-05 0.00027611 PUT PTPN5 -1.322763 9.23E-05 0.00028844 PUT FAM81B 1.38188421 0.00013468 0.00040248 PUT ZBTB20-AS5 1.26566877 0.00013102 0.00039272 PUT TNFRSF11B 1.33416251 0.00014288 0.0004242 PUT GAD2 -1.3163714 9.21E-05 0.00028791 PUT KCNJ1 -1.1838585 0.00013975 0.00041599 PUT LOC642366 -1.1612138 0.00014543 0.00043082 PUT SOST 1.48331124 0.00012511 0.00037699 PUT FER1L6-AS2 -1.0384716 0.0001471 0.00043529 PUT RPRML -1.1186537 0.00012015 0.00036355 PUT PHYHIP -1.0286228 0.00011004 0.00033709 PUT LYPD6B -1.0990401 0.00016027 0.00046949 PUT RDH8 1.12874869 0.00016599 0.00048401 PUT NR1I2 -1.0697346 0.00015726 0.00046168 PUT LOC153910 1.07696594 0.00015806 0.00046375 PUT CCDC168 1.70913535 0.00015195 0.00044796 PUT IL1R2 1.83792935 0.00015711 0.00046138 PUT KCNJ4 -1.2928253 0.00010964 0.00033624 PUT DLEC1 1.00009735 0.00013821 0.00041186 PUT SLC17A4 1.19940637 0.00018093 0.00052349 PUT RIMBP3 -1.3815093 0.00018653 0.00053789 PUT CHRNG 1.00947266 0.00019112 0.00054989 PUT RNA5-8SN5 1.46260988 0.00014085 0.00041881 PUT FLT4 -1.0744288 0.00013003 0.00039007 PUT C7orf57 -1.1645044 0.00019532 0.00056036 PUT LINC01589 1.17660339 0.00019379 0.00055696 PUT ISLR2 -1.0461271 0.00013471 0.00040252 PUT LINC02185 1.11789174 0.00021678 0.00061357 PUT PGM5P4-AS1 -1.3779851 0.00020186 0.00057685 PUT PDILT 1.30210698 0.00019745 0.00056517 PUT GRIN1 -1.1038922 0.00015246 0.00044933 PUTZFP91-CNTF 2.53955073 0.00020435 0.00058289 PUT C12orf71 1.15584973 0.00023867 0.00066776 PUT SNORA73B 1.59104278 0.00023286 0.00065346 PUT DRD2 -1.2167843 0.00015268 0.00044985 PUT HSPA6 2.12062662 0.0001952 0.00056023 PUT PRTN3 -1.0558254 0.00025978 0.00071929 PUT HLA-DOB -1.1385758 0.00025261 0.00070097 PUT MIR8082 1.06636401 0.00025935 0.00071821 PUT SYNPR -1.2898295 0.00016864 0.00049085 PUT HES5 -1.1077826 0.00024903 0.00069246 PUT SAPCD1 -1.1900224 0.00027005 0.00074545 PUT TH -1.3625821 0.00024211 0.00067637 PUT CAMK1G -1.0699441 0.00016678 0.00048588 PUT FAT2 -1.180598 0.00021985 0.00062143 PUT LY6K 1.04001549 0.00028795 0.00079048 PUT IGFBP3 1.2925394 0.00023358 0.00065514 PUT CATSPERD 1.31282579 0.0002911 0.00079799 PUT SLCO4A1-AS1 1.37113593 0.00030421 0.00082985 PUT DLX5 -1.0104342 0.00024434 0.00068191 PUT LINC00930 1.13583716 0.00030795 0.00083836 PUT GDF15 1.24847384 0.00031771 0.0008611 PUT SCARA5 -1.18882 0.00032041 0.00086731 PUT NFIA-AS1 1.09855472 0.00032004 0.00086656 PUT ISL1 -1.0149921 0.00030513 0.00083191 PUT HNF1A 1.07852956 0.00032241 0.00087235 PUT H4C4 1.61031136 0.00031702 0.00085997 PUT SNORA73A 1.8396233 0.00036895 0.00098288 PUT ARHGAP40 -1.082966 0.00037356 0.00099319 PUT GNA14-AS1 1.06779898 0.00037101 0.00098751 PUT RNU2-1 1.06399749 0.00023669 0.00066318 PUT SNORA81 2.03910814 0.00037119 0.00098777 PUT RNA5S1 1.82649168 0.00024659 0.00068717 PUT F13A1 -1.0235348 0.00031573 0.00085671 PUT NBPF4 -1.7602419 0.00038215 0.00101489 PUT TMX2- -1.4326243 0.0003921 0.00103841 PUT CTNND1 GPR6 -1.2901172 0.00026549 0.00073391 PUT SV2C -1.1279167 0.00026354 0.00072895 PUT SLPI 1.23834154 0.00044429 0.00116139 PUT SERPINC1 1.06251309 0.00046147 0.00120332 PUT LUM -1.2018547 0.000487 0.00126039 PUT G0S2 1.22729268 0.00043151 0.00113086 PUT TERT -1.1039116 0.00049772 0.00128427 PUTPPIAL4E 1.27717319 0.00052469 0.00134455 PUT MIR5689HG 1.03651364 0.00053938 0.00137809 PUT LOC101929341 1.00938173 0.00054035 0.00137998 PUT CT45A1 -1.823206 0.0005073 0.00130615 PUT PEX5L-AS2 1.0912417 0.00055006 0.00140237 PUT SERPINA3 1.26655694 0.00034097 0.0009167 PUT TCL1B 1.06078324 0.00060595 0.00152701 PUT GZMM 1.06833996 0.00062936 0.00158014 PUT SNORA54 1.22588342 0.00062857 0.00157837 PUT IL18R1 1.12756224 0.00065841 0.00164331 PUT ALOX15B 1.19141808 0.00075419 0.00185407 PUT IL1RL1 1.65469559 0.00059435 0.00149997 PUT DCLK3 -1.0394887 0.00051027 0.00131256 PUT IL13RA2 -1.022344 0.00070927 0.0017557 PUT OTOF -1.1299066 0.00045169 0.00117962 PUT S100A9 1.53128835 0.00067018 0.00166944 PUT CELF3 -1.0004157 0.00049729 0.00128333 PUT GJA9 1.87589505 0.00078916 0.00193079 PUT SERPINA5 1.25341737 0.00077351 0.0018969 PUT DNAAF3 1.11861027 0.000962 0.00229857 PUT COCH -1.2441894 0.00061483 0.00154714 PUT RNU4-2 1.13083821 0.00076125 0.00186926 PUT SYNDIG1L -1.013332 0.00077098 0.0018912 PUT BCL2A1 1.23340304 0.00127434 0.00294876 PUT SNORA53 1.05492832 0.00134955 0.00310389 PUT PCK1 1.0616716 0.0011894 0.00276978 PUT MIR4451 1.17174492 0.00135978 0.00312287 PUT KCNQ1DN -1.0656709 0.00143057 0.00326767 PUT HGD 1.02589809 0.00144643 0.00330111 PUT RNA28SN5 1.04733261 0.00126115 0.00292144 PUT PRKCG -1.0839791 0.00093658 0.0022449 PUT SNORD15B 1.26521154 0.00184713 0.00410267 PUT CLDN19 1.19974281 0.0019667 0.00433981 PUT LGR6 -1.17907 0.00178765 0.00398315 PUT RNU5A-1 1.04837947 0.00186403 0.00413683 PUT RNU5B-1 1.00988912 0.0017944 0.00399677 PUT CSF3 1.79654487 0.00212954 0.00466335 PUT VSNL1 -1.0955815 0.00128029 0.00296181 PUT NTS -1.3374614 0.00233355 0.00505473 PUT SNORA20 1.16223065 0.00261775 0.00559376 PUT WDR38 1.18829696 0.00236866 0.00512204 PUT ATE1-AS1 1.05615617 0.00231871 0.00502776 PUTRNVU1-7 2.96494105 0.00207878 0.00456486 PUT SNORA74B 1.04693763 0.00283885 0.00600101 PUT NPB -1.1740481 0.00299414 0.00628905 PUT PKHD1L1 1.01950123 0.00310813 0.00649828 PUT MMP23B 1.09553686 0.00323668 0.00673516 PUT FAM72D -1.172596 0.00346588 0.00715719 PUT LOC100130238 1.48845322 0.00353232 0.0072825 PUT LCN6 1.04306086 0.00405094 0.00821525 PUT GPR88 -1.1729627 0.0019645 0.00433547 PUT TPSD1 1.13575507 0.00416228 0.00841676 PUT SNORD14E 1.15667444 0.00423389 0.00854247 PUT GOLGA8F 1.29169193 0.00457652 0.00915786 PUT OR7A5 1.4625078 0.00473519 0.00943956 PUT TAS2R39 1.05745654 0.00491128 0.00974454 PUT CT45A6 -2.0504158 0.00477479 0.00950751 PUT MIR3648-1 1.06360843 0.00421849 0.00851773 PUT C1orf167 1.05427748 0.00469579 0.0093679 PUT TVP23C- -1.3924563 0.00562637 0.01101147 PUT CDRT4 CXCR1 1.33034009 0.00603917 0.0117323 PUT CD177 1.25048312 0.00600147 0.01166503 PUT HLA-DQA2 -1.7158686 0.00712644 0.01360725 PUT NBPF6 -1.1941476 0.00728429 0.01387993 PUT RNVU1-18 1.05245263 0.00374189 0.00766133 PUT NLGN4Y-AS1 1.11738051 0.00796664 0.01503377 PUT MAP3K19 1.07355153 0.00732986 0.01395416 PUT ELOA3B 1.13184684 0.00996809 0.01835458 PUT PSAPL1 1.10284784 0.01274318 0.02288518 PUT RIMBP3B -1.3336146 0.0131512 0.02354523 PUT LRRC71 1.0108154 0.0101077 0.01858822 PUT OR7C1 1.00526257 0.01361099 0.02424414 PUT CCL19 -1.1180789 0.01285986 0.02306852 PUT MEPE -1.100718 0.01475473 0.02604681 PUT FRG2 1.30330044 0.01829652 0.03152821 PUT IGLL5 1.25426324 0.03002617 0.04910646 PUT CXCL10 -1.0300091 0.02907796 0.04770775 PUT TTR 1.62751247 0.02737066 0.04516029 PUT HBB -1.0010594 0.02729736 0.04505085 PUT GPCPD1 -1.3723731 2.04E-17 3.87E-13 CAU DHRS11 -1.08485 8.82E-16 8.37E-12 CAU BFSP1 -1.32844 1.46E-15 9.22E-12 CAU CIRBP -1.1850312 5.09E-15 1.56E-11 CAU RBM3 -1.2100339 6.67E-15 1.58E-11 CAUJMJD6 1.24735168 1.62E-14 2.66E-11 CAU KCNE4 1.05025416 1.83E-14 2.66E-11 CAU NFKB2 1.20507155 1.91E-14 2.66E-11 CAU TRIP10 1.31114985 2.36E-14 2.98E-11 CAU COL27A1 1.38418504 3.36E-14 3.67E-11 CAU NUP210L 1.90579871 2.72E-14 3.23E-11 CAU TCAP 1.37506186 1.17E-13 1.11E-10 CAU PCYOX1L -1.2129692 2.01E-13 1.82E-10 CAU MRPS6 1.15539141 2.49E-13 2.15E-10 CAU RCC1 1.01822244 2.79E-13 2.30E-10 CAU ANGPT2 1.50548965 3.34E-13 2.64E-10 CAU SLCO4A1 2.65056086 4.10E-13 2.78E-10 CAU H3C15 1.72434806 3.74E-13 2.68E-10 CAU PHF21B 1.05820358 5.18E-13 3.07E-10 CAU BCL6 1.13097151 7.15E-13 3.57E-10 CAU H4C15 1.09378178 8.10E-13 3.84E-10 CAU TRAM1L1 -1.0949859 8.76E-13 3.96E-10 CAU GCNA 1.34185193 8.31E-13 3.85E-10 CAU GPR4 2.0045704 9.34E-13 4.12E-10 CAU PLK4 -1.5697162 4.66E-13 2.86E-10 CAU SMTN 1.08622727 1.31E-12 4.98E-10 CAU C7orf61 2.08538072 1.39E-12 5.19E-10 CAU LEAP2 1.00386726 1.22E-12 4.90E-10 CAU MKNK2 1.32446508 2.40E-12 7.34E-10 CAU BNIPL 1.2525553 2.39E-12 7.34E-10 CAU SLC5A3 1.30941651 3.41E-12 8.86E-10 CAU SERPINF2 1.56005546 2.65E-12 7.69E-10 CAU CERNA1 -1.4829476 2.48E-12 7.36E-10 CAU SPR 1.39012838 5.38E-12 1.23E-09 CAU SERTAD1 1.01881398 5.77E-12 1.27E-09 CAU DYNC1I1 -1.0484776 7.27E-12 1.48E-09 CAU MAFF 1.86467249 8.94E-12 1.71E-09 CAU MEX3A 1.01906392 8.46E-12 1.69E-09 CAU CHRM2 -1.6490179 1.02E-11 1.91E-09 CAU PRSS8 1.06841689 8.82E-12 1.71E-09 CAU SLC10A4 -2.0599396 1.27E-11 2.30E-09 CAU CCDC62 1.02387864 1.47E-11 2.54E-09 CAU IL17RB 1.03055278 1.91E-11 3.04E-09 CAU NUPR1 1.34803939 1.93E-11 3.05E-09 CAU HOOK2 1.00631488 2.02E-11 3.12E-09 CAU NAA80 -1.2496817 2.16E-11 3.18E-09 CAU LPIN3 1.08651412 2.19E-11 3.19E-09 CAUCHORDC1 1.44773459 2.20E-11 3.19E-09 CAU TNFRSF10D 1.84670106 2.12E-11 3.18E-09 CAU C1orf94 -2.3825779 5.66E-12 1.27E-09 CAU DDIT4 1.64986441 2.44E-11 3.43E-09 CAU LSMEM1 1.26770852 1.90E-11 3.04E-09 CAU ABCA11P -1.0702344 2.47E-11 3.44E-09 CAU CDKL1 1.01497157 2.82E-11 3.76E-09 CAU NTRK1 -2.0147576 3.75E-11 4.78E-09 CAU FOSL1 1.25858401 4.26E-11 5.22E-09 CAU DCTN1-AS1 -1.0510665 5.05E-11 5.99E-09 CAU DCAF12L2 -2.0512206 2.23E-11 3.21E-09 CAU CCDC36 1.41698611 4.54E-11 5.53E-09 CAU LINC00513 1.12834799 6.29E-11 7.24E-09 CAU FAM151A 1.24865952 6.79E-11 7.67E-09 CAU MIR639 1.21053708 8.23E-11 8.83E-09 CAU MAP10 -1.3214528 6.93E-11 7.67E-09 CAU HSPB1 2.15003778 8.98E-11 9.37E-09 CAU KDM4D -1.3453155 6.09E-11 7.05E-09 CAU GPD1 -1.5506903 9.42E-11 9.67E-09 CAU LRG1 1.2722891 8.01E-11 8.69E-09 CAU MLKL 1.55381199 1.04E-10 1.04E-08 CAU SERPINH1 2.4690271 1.15E-10 1.12E-08 CAU SPACA6 1.02857406 1.32E-10 1.24E-08 CAU CEL 1.16743441 1.18E-10 1.13E-08 CAU FOXP1-AS1 1.17742523 1.04E-10 1.04E-08 CAU SMIM10L2B -1.2887804 1.52E-10 1.36E-08 CAU TJP3 1.32908014 1.54E-10 1.36E-08 CAU LOC441086 -1.2303615 1.54E-10 1.36E-08 CAU LINC01310 -1.5536442 1.76E-10 1.45E-08 CAU DNAJB1 2.14535584 2.13E-10 1.63E-08 CAU ECEL1 -2.3471058 2.48E-10 1.85E-08 CAU CLDN15 1.00911551 2.57E-10 1.90E-08 CAU RIPOR3 1.12765737 3.18E-10 2.22E-08 CAU BAG3 1.76721059 3.16E-10 2.21E-08 CAU ITFG1 -1.0436116 3.23E-10 2.23E-08 CAU AMY2A -1.9978068 1.97E-10 1.55E-08 CAU INSM2 -1.5283861 2.84E-10 2.03E-08 CAU NEBL-AS1 -1.5780762 1.97E-10 1.55E-08 CAU MIA 2.00016607 2.04E-10 1.57E-08 CAU CYGB -1.3313795 4.71E-10 2.83E-08 CAU PCSK1 -1.8441074 5.11E-10 2.97E-08 CAU CYP4X1 -1.2048881 5.59E-10 3.17E-08 CAUSMOC2 -1.1423849 5.50E-10 3.13E-08 CAU EVC2 1.41009999 5.10E-10 2.97E-08 CAU NXPH1 -1.2985177 5.80E-10 3.28E-08 CAU NXPH2 -2.2518536 1.78E-10 1.45E-08 CAU STH 1.25524767 4.81E-10 2.86E-08 CAU SH2D7 1.49204397 3.90E-10 2.49E-08 CAU SLC5A7 -2.7174767 5.87E-10 3.30E-08 CAU NPC1L1 2.12114559 3.52E-10 2.35E-08 CAU CLEC2L -1.3747119 6.39E-10 3.49E-08 CAU SCUBE3 1.06135041 6.26E-10 3.46E-08 CAU TECTA -1.169304 8.24E-10 4.20E-08 CAU PCAT19 1.3548122 8.22E-10 4.20E-08 CAU ATOH8 1.18863134 7.98E-10 4.10E-08 CAU RCAN2 -1.2914943 7.93E-10 4.08E-08 CAU GDPD3 1.04172407 8.09E-10 4.14E-08 CAU LOC100506274 -1.8379969 4.17E-10 2.58E-08 CAU CMPK2 -1.0183068 9.02E-10 4.52E-08 CAU GPR52 -2.4111866 8.79E-10 4.42E-08 CAU KAZALD1 -1.0704608 7.61E-10 3.95E-08 CAU KIRREL2 -1.3316264 8.76E-10 4.42E-08 CAU LANCL1 -1.0120211 1.06E-09 5.14E-08 CAU PLAC4 1.39818231 1.09E-09 5.25E-08 CAU LINC01338 1.51084587 1.09E-09 5.25E-08 CAU MALAT1 1.24541508 1.14E-09 5.40E-08 CAU ETV4 1.05002366 1.11E-09 5.30E-08 CAU EDN3 -1.4174065 1.32E-09 5.93E-08 CAU SIX4 1.40302526 1.23E-09 5.62E-08 CAU P4HA1 1.17856776 1.30E-09 5.85E-08 CAU SYS1- -1.3871575 1.45E-09 6.38E-08 CAU DBNDD2 SLC17A8 -1.7448531 1.39E-09 6.22E-08 CAU H3C4 1.38727629 1.09E-09 5.25E-08 CAU CRYM-AS1 1.04673651 1.41E-09 6.27E-08 CAU HIF3A 1.0410077 1.66E-09 7.02E-08 CAU CD38 -1.1845191 1.74E-09 7.25E-08 CAU SERPINB11 1.79780862 9.06E-10 4.53E-08 CAU ZBTB16 1.34823419 1.70E-09 7.12E-08 CAU LOC284933 2.13470488 1.30E-09 5.86E-08 CAU PRR26 1.1935552 1.89E-09 7.75E-08 CAU LHFPL3 -1.2648853 2.07E-09 8.20E-08 CAU C2orf80 -1.2630113 2.23E-09 8.62E-08 CAU MDH1 -1.1197601 2.15E-09 8.42E-08 CAU NHLRC1 -1.214925 1.96E-09 7.84E-08 CAUFIBCD1 -1.6953657 1.90E-09 7.76E-08 CAU ROBO2 -1.2267721 2.22E-09 8.62E-08 CAU FRAS1 -1.2038609 2.67E-09 9.82E-08 CAU RGL3 1.08268946 2.96E-09 1.06E-07 CAU TMEFF1 -1.4213456 3.06E-09 1.09E-07 CAU CKM 1.83227997 1.98E-09 7.87E-08 CAU P4HA2 1.30354891 3.21E-09 1.13E-07 CAU LOC101928123 1.23604973 2.99E-09 1.07E-07 CAU KRT5 -1.6797165 2.30E-09 8.88E-08 CAU HSPA1A 2.27797785 3.29E-09 1.15E-07 CAU SHOC1 1.086694 3.47E-09 1.20E-07 CAU NEAT1 1.47341534 3.39E-09 1.18E-07 CAU LHX8 -2.3488129 3.23E-09 1.14E-07 CAU CYP26A1 -2.245409 2.14E-09 8.39E-08 CAU KCNE5 -1.2873944 3.83E-09 1.30E-07 CAU HSPA1B 2.10823557 3.79E-09 1.29E-07 CAU ZBED6 1.10407521 3.89E-09 1.32E-07 CAU LINC01134 1.31854664 2.71E-09 9.93E-08 CAU DSG1 -1.7754555 1.60E-09 6.83E-08 CAU TUBB4A -1.0199219 4.34E-09 1.43E-07 CAU HPRT1 -1.0867896 4.26E-09 1.42E-07 CAU BACE2 1.13363902 4.80E-09 1.55E-07 CAU CCNA2 1.08017099 4.96E-09 1.59E-07 CAU HS6ST2 -1.672455 5.47E-09 1.73E-07 CAU TNFSF14 1.08249033 5.29E-09 1.67E-07 CAU HSPB9 1.12419722 6.59E-09 2.01E-07 CAU GKAP1 1.02323554 7.74E-09 2.26E-07 CAU CLEC2B 1.27807678 8.39E-09 2.39E-07 CAU NRIP3 -1.2146875 7.70E-09 2.25E-07 CAU C9orf153 1.53335607 5.84E-09 1.82E-07 CAU HSPA6 3.34050447 9.45E-09 2.63E-07 CAU TEAD2 1.01775337 9.54E-09 2.65E-07 CAU NDC80 1.19544054 9.26E-09 2.58E-07 CAU TRPC3 -1.5942923 1.01E-08 2.77E-07 CAU TUBB3 -1.0861575 9.15E-09 2.57E-07 CAU PPP4R4 -1.1216634 1.00E-08 2.77E-07 CAU CA4 -1.3389896 1.09E-08 2.93E-07 CAU SLC10A1 1.61676952 7.39E-09 2.17E-07 CAU GPR61 -1.1386335 1.16E-08 3.08E-07 CAU TACR1 -1.7972532 1.15E-08 3.05E-07 CAU SPHKAP -1.463641 1.20E-08 3.17E-07 CAU USP46-AS1 -1.3195712 1.01E-08 2.77E-07 CAUIKBKE -1.0962898 1.37E-08 3.50E-07 CAU GPRC5A 1.35020661 1.31E-08 3.37E-07 CAU GLTPD2 -1.1777472 1.35E-08 3.47E-07 CAU NUGGC 1.05509967 1.53E-08 3.86E-07 CAU RD3 1.09313936 1.50E-08 3.80E-07 CAU COL25A1 -1.6545357 1.81E-08 4.43E-07 CAU ZC3H12A 1.24035557 1.81E-08 4.43E-07 CAU LINC01561 1.01340935 2.15E-08 5.00E-07 CAU ATP5MGL 1.10503909 1.98E-08 4.72E-07 CAU SGO1 1.21160519 1.72E-08 4.24E-07 CAU MT2A 1.06330418 1.99E-08 4.72E-07 CAU ABCG4 -1.0391599 2.30E-08 5.27E-07 CAU SDR16C5 -1.3540863 2.07E-08 4.86E-07 CAU OPCML -1.2648591 2.13E-08 4.97E-07 CAU TPBGL -1.5242299 2.46E-08 5.59E-07 CAU MAP3K5-AS1 1.10845672 1.99E-08 4.72E-07 CAU DOCK9-DT -1.3009753 2.53E-08 5.69E-07 CAU PCLAF 1.17998705 2.87E-08 6.32E-07 CAU FAM156B -2.7902283 3.18E-08 6.82E-07 CAU CLVS1 -1.3531197 3.13E-08 6.75E-07 CAU RNF128 -1.2539519 3.36E-08 7.12E-07 CAU CTRC 1.13957431 3.11E-08 6.73E-07 CAU TOMM70 -1.0212671 3.00E-08 6.55E-07 CAU NELL1 -1.3637308 3.56E-08 7.45E-07 CAU H1-2 1.0451838 3.42E-08 7.21E-07 CAU ARHGEF9 -1.0263905 3.18E-08 6.82E-07 CAU VGF -1.8009222 3.26E-08 6.94E-07 CAU FOSL2 1.06532535 3.14E-08 6.77E-07 CAU COL6A5 -1.8886652 1.85E-08 4.50E-07 CAU CHAT -2.4815272 3.55E-08 7.44E-07 CAU LCA10 1.16620971 3.22E-08 6.87E-07 CAU OLFM3 -1.4482847 3.77E-08 7.73E-07 CAU PTPRR -1.3044162 3.82E-08 7.78E-07 CAU CX3CL1 -1.0614537 3.39E-08 7.16E-07 CAU PLPPR4 -1.4404444 3.80E-08 7.75E-07 CAU SLC7A11-AS1 1.506374 4.50E-08 8.78E-07 CAU HAPLN1 -1.432953 4.25E-08 8.41E-07 CAU SYT13 -1.4629647 4.15E-08 8.25E-07 CAU MAGEE1 -1.2524113 4.14E-08 8.25E-07 CAU PKP1 -1.4374166 4.33E-08 8.51E-07 CAU MICB 1.15294934 4.98E-08 9.49E-07 CAU LOC158434 1.2031047 4.90E-08 9.37E-07 CAUDSCAM-AS1 1.33667644 5.10E-08 9.65E-07 CAU LBX2 1.75022815 2.59E-08 5.80E-07 CAU RAB20 1.06299464 5.51E-08 1.02E-06 CAU DRD5 -1.3905389 5.45E-08 1.01E-06 CAU SLC35G5 1.25090483 5.43E-08 1.01E-06 CAU ARHGAP20 -1.2246323 5.18E-08 9.75E-07 CAU LINC02210- -2.5782689 3.60E-08 7.51E-07 CAU CRHR1 SCG5 -1.1759331 5.14E-08 9.71E-07 CAU MT1M 1.28242049 5.37E-08 1.00E-06 CAU SOCS3 2.21089062 5.93E-08 1.08E-06 CAU SORCS3 -1.0860581 5.91E-08 1.08E-06 CAU CRYAB 1.09602668 6.29E-08 1.13E-06 CAU CAPN12 1.33396232 5.91E-08 1.08E-06 CAU TMEM132D -1.1430819 6.47E-08 1.15E-06 CAU GOLGA8J -1.0304605 6.99E-08 1.22E-06 CAU FAM167B 1.71905388 6.21E-08 1.12E-06 CAU RASGRF1 -1.0817905 6.22E-08 1.12E-06 CAU DEPP1 1.67066326 6.24E-08 1.12E-06 CAU PNMA3 -1.0432638 6.52E-08 1.15E-06 CAU KCNAB1 -1.5472418 6.42E-08 1.14E-06 CAU COL26A1 -1.17024 7.27E-08 1.25E-06 CAU SYT2 -1.7926528 6.60E-08 1.17E-06 CAU LCN10 2.04592113 5.58E-08 1.03E-06 CAU PSPN 1.45435644 4.83E-08 9.27E-07 CAU DNMT3L 2.06665394 3.18E-08 6.82E-07 CAU SLC17A9 1.18257489 7.83E-08 1.32E-06 CAU RIT2 -1.1918451 8.71E-08 1.43E-06 CAU ERN2 1.00080969 8.68E-08 1.43E-06 CAU PHF24 -1.2893541 7.66E-08 1.30E-06 CAU MAL2 -1.5632676 7.99E-08 1.34E-06 CAU PRKX 1.01514662 8.09E-08 1.35E-06 CAU PTPRN2 -1.1032969 8.29E-08 1.38E-06 CAU SLC22A14 1.2913112 7.52E-08 1.28E-06 CAU REP15 1.33118779 7.78E-08 1.31E-06 CAU INSYN1-AS1 -1.384145 7.68E-08 1.30E-06 CAU HROB 1.1311082 9.68E-08 1.56E-06 CAU XK -1.1437583 1.05E-07 1.66E-06 CAU RGS7 -1.1590851 9.17E-08 1.50E-06 CAU EIF4EBP1 1.12592473 1.09E-07 1.70E-06 CAU RFPL1 -1.2750109 1.01E-07 1.61E-06 CAU ARL4D -1.1923097 1.05E-07 1.66E-06 CAU PCDHAC2 -1.0293844 1.02E-07 1.62E-06 CAURAX2 1.15352047 9.60E-08 1.55E-06 CAU NOS1 -1.0049575 9.68E-08 1.56E-06 CAU LINC01730 1.2281773 9.93E-08 1.59E-06 CAU NBPF10 1.04661419 9.97E-08 1.60E-06 CAU PDP1 -1.1621004 1.01E-07 1.61E-06 CAU HSP90AA1 1.17791619 1.18E-07 1.81E-06 CAU SYTL5 -1.4234111 1.14E-07 1.76E-06 CAU LNX1 -1.2766892 1.13E-07 1.74E-06 CAU CKMT1A -1.5143657 1.13E-07 1.75E-06 CAU C20orf173 1.6734034 6.46E-08 1.15E-06 CAU MTHFD2 1.07553595 1.25E-07 1.89E-06 CAU SH3RF2 -1.5126216 1.26E-07 1.90E-06 CAU LOC101927770 1.08570341 1.42E-07 2.09E-06 CAU NSF -1.2494597 1.23E-07 1.86E-06 CAU POU2F3 1.25233017 1.41E-07 2.09E-06 CAU SPDEF -1.3171381 1.05E-07 1.66E-06 CAU KRT86 -1.3457456 1.08E-07 1.69E-06 CAU MYH6 -1.2200282 1.07E-07 1.69E-06 CAU SLC7A4 -1.465907 1.56E-07 2.26E-06 CAU PHKA1-AS1 1.18650032 1.10E-07 1.72E-06 CAU DNAJB5-DT 1.89984443 7.05E-08 1.22E-06 CAU MPEG1 -1.0541507 1.56E-07 2.27E-06 CAU TRPV6 -1.0282895 1.53E-07 2.23E-06 CAU GLT1D1 -1.255996 1.45E-07 2.13E-06 CAU ALB -1.3769823 1.33E-07 1.98E-06 CAU LOC339666 1.07405582 1.41E-07 2.08E-06 CAU MPO -1.117334 1.64E-07 2.34E-06 CAU RHOV -1.6233567 1.24E-07 1.88E-06 CAU CPNE4 -1.3718147 1.68E-07 2.38E-06 CAU ZSCAN4 1.02625884 1.84E-07 2.56E-06 CAU UBE2T -1.043973 1.87E-07 2.59E-06 CAU LOC283038 1.33278724 1.72E-07 2.44E-06 CAU CEBPD 1.46405173 1.67E-07 2.38E-06 CAU RAB40A -1.2850839 1.77E-07 2.49E-06 CAU LUCAT1 1.20412497 1.86E-07 2.57E-06 CAU FBN3 -1.0107576 1.97E-07 2.69E-06 CAU LOC285847 1.30692787 1.56E-07 2.27E-06 CAU ACY3 -1.6271454 2.06E-07 2.78E-06 CAU EGR2 -1.5046788 2.19E-07 2.91E-06 CAU TMEM179 -1.2481305 2.04E-07 2.75E-06 CAU MIR5690 2.07927043 9.76E-08 1.57E-06 CAU HMOX1 1.07120784 1.98E-07 2.70E-06 CAUTUBA8 -1.2557469 1.99E-07 2.71E-06 CAU SNORA77 2.33140815 7.08E-08 1.23E-06 CAU TDRD5 -1.4231579 2.29E-07 2.99E-06 CAU SLC15A1 1.07617786 2.39E-07 3.10E-06 CAU LINC01006 -1.1140438 2.31E-07 3.01E-06 CAU VSTM5 -1.4529906 2.47E-07 3.16E-06 CAU DACH2 -1.2426338 2.67E-07 3.33E-06 CAU SGK2 -1.0929523 2.69E-07 3.34E-06 CAU ATAD3C 1.09013335 2.65E-07 3.31E-06 CAU MAB21L3 1.08697256 2.47E-07 3.16E-06 CAU MYBPC1 1.0137194 2.47E-07 3.16E-06 CAU HRG 1.2455654 3.05E-07 3.69E-06 CAU C8orf49 1.08793794 3.00E-07 3.65E-06 CAU GJA3 -1.805146 2.46E-07 3.16E-06 CAU PKDCC 1.01082536 3.22E-07 3.85E-06 CAU BCL3 1.1069034 3.23E-07 3.86E-06 CAU LINC01843 1.11240224 2.41E-07 3.11E-06 CAU ULK4P1 -1.1384294 3.08E-07 3.72E-06 CAU BMP4 1.1156364 3.27E-07 3.90E-06 CAU NSG1 -1.3941945 2.84E-07 3.50E-06 CAU KIF1C 1.02953302 3.14E-07 3.78E-06 CAU HNF1A 1.5916663 1.73E-07 2.44E-06 CAU MIR8066 1.88833657 2.41E-07 3.11E-06 CAU HAR1A -1.1544865 3.53E-07 4.12E-06 CAU DKK2 -1.3409312 2.93E-07 3.59E-06 CAU FKBP4 1.02656259 3.15E-07 3.79E-06 CAU EGR1 -1.0509317 3.17E-07 3.81E-06 CAU LINC02288 1.08762983 3.88E-07 4.46E-06 CAU CACNG1 -1.5684672 3.33E-07 3.95E-06 CAU CSRP3 1.45010014 2.20E-07 2.92E-06 CAU LINC00311 1.35628709 3.86E-07 4.45E-06 CAU NETO1 -1.3105901 3.48E-07 4.08E-06 CAU OTX2-AS1 1.15505867 3.82E-07 4.41E-06 CAU LDB2 -1.0374237 3.39E-07 4.01E-06 CAU GPR158 -1.3339347 3.43E-07 4.03E-06 CAU KIRREL3-AS2 1.23334664 4.10E-07 4.66E-06 CAU ALOX15B 1.81870217 3.73E-07 4.32E-06 CAU TMEM196 -1.1730465 4.67E-07 5.18E-06 CAU LINC00261 1.65819882 4.84E-07 5.33E-06 CAU SVOP -1.4397641 4.04E-07 4.61E-06 CAU REM2 -1.355517 5.07E-07 5.53E-06 CAU LINC01119 -1.2817381 4.59E-07 5.12E-06 CAUSTAT4 -1.1873089 5.06E-07 5.52E-06 CAU CPXM1 -1.6248621 3.74E-07 4.33E-06 CAU LOC100129620 -1.3396271 3.36E-07 3.98E-06 CAU SOX1-OT -1.1207678 5.23E-07 5.67E-06 CAU GREM2 -1.0955978 5.05E-07 5.52E-06 CAU C11orf87 -1.3709911 4.69E-07 5.19E-06 CAU PRH1- -1.674113 4.88E-07 5.37E-06 CAU TAS2R14 HNF1B 1.17008585 4.90E-07 5.38E-06 CAU ANKRD37 1.08723162 4.96E-07 5.43E-06 CAU SLC35G6 1.2624455 4.49E-07 5.03E-06 CAU IGFBPL1 -1.495271 5.71E-07 6.05E-06 CAU LHCGR 1.01285449 5.41E-07 5.82E-06 CAU SMIM17 -1.1011061 6.17E-07 6.43E-06 CAU IFITM2 1.0632689 5.09E-07 5.54E-06 CAU LOC101927661 1.13072206 5.76E-07 6.09E-06 CAU LINC00824 1.10352435 6.27E-07 6.52E-06 CAU TUSC3 -1.0205604 5.24E-07 5.67E-06 CAU C1orf210 1.19243816 5.42E-07 5.82E-06 CAU NPY5R -1.4087947 6.57E-07 6.78E-06 CAU CALB1 -1.5963038 5.72E-07 6.06E-06 CAU FAM237A -1.5558523 6.12E-07 6.39E-06 CAU RPE65 -2.0935123 5.35E-07 5.76E-06 CAU EPB41L4A-DT -1.0348712 6.31E-07 6.54E-06 CAU UPK2 -1.3448939 5.42E-07 5.82E-06 CAU PARM1 -1.2141891 5.85E-07 6.17E-06 CAU SLC18A3 -1.8701164 7.28E-07 7.32E-06 CAU AMBN -2.2478828 7.18E-07 7.26E-06 CAU LEXM -1.4520061 5.84E-07 6.16E-06 CAU KIF12 -1.4594326 7.74E-07 7.69E-06 CAU EPHA8 -1.2025676 7.49E-07 7.50E-06 CAU SV2B -1.20726 6.34E-07 6.57E-06 CAU SALRNA2 1.37055594 5.68E-07 6.03E-06 CAU LOC102724163 1.05643056 8.09E-07 7.95E-06 CAU CPZ -1.3671292 6.95E-07 7.08E-06 CAU CDA 1.34684017 8.01E-07 7.89E-06 CAU NCR1 1.3492252 5.67E-07 6.03E-06 CAU PRR23C 1.14144576 6.82E-07 6.98E-06 CAU GZMM 1.57989039 5.99E-07 6.29E-06 CAU CRH -1.4582052 8.48E-07 8.27E-06 CAU GBX2 -1.1481035 8.74E-07 8.48E-06 CAU LINC01616 -1.3812661 8.43E-07 8.24E-06 CAU GP2 1.11577881 8.21E-07 8.04E-06 CAUADAM23 -1.09829 7.14E-07 7.24E-06 CAU PADI1 -1.4831119 6.66E-07 6.84E-06 CAU KLHL13 -1.1873069 7.58E-07 7.56E-06 CAU CLLU1 1.10516272 8.51E-07 8.28E-06 CAU MS4A14 1.41253692 8.65E-07 8.40E-06 CAU TLDC2 1.00544263 9.20E-07 8.86E-06 CAU PNOC -1.3911559 9.33E-07 8.94E-06 CAU KCNK2 -1.2081334 8.91E-07 8.61E-06 CAU RASGRP2 -1.0118989 8.71E-07 8.46E-06 CAU KDF1 2.19081093 6.61E-07 6.81E-06 CAU GATA2-AS1 1.10978909 1.11E-06 1.03E-05 CAU PRMT8 -1.3230638 9.27E-07 8.91E-06 CAU ATP2B3 -1.1136023 8.98E-07 8.66E-06 CAU WASF1 -1.1246733 9.09E-07 8.76E-06 CAU SCN4B -1.7162532 9.37E-07 8.98E-06 CAU KRT26 1.41729904 1.16E-06 1.07E-05 CAU FLJ31356 1.04778198 1.08E-06 1.01E-05 CAU P2RY12 -1.1498818 1.11E-06 1.03E-05 CAU PARD6G-AS1 1.1416496 1.18E-06 1.08E-05 CAU CLSTN2 -1.0551225 9.66E-07 9.18E-06 CAU NIBAN3 1.54215821 9.78E-07 9.28E-06 CAU CHRNB2 -1.4336223 1.03E-06 9.73E-06 CAU SLC7A3 -1.5979709 1.05E-06 9.86E-06 CAU PNLIPRP1 1.02168762 1.23E-06 1.11E-05 CAU LILRA5 1.26680707 1.28E-06 1.15E-05 CAU SLITRK3 -1.0622326 1.15E-06 1.06E-05 CAU IGFN1 -1.4227511 1.37E-06 1.21E-05 CAU LRRC14B -1.6008283 9.31E-07 8.94E-06 CAU GGT6 1.01134954 1.36E-06 1.20E-05 CAU SYT16 -1.0064429 1.09E-06 1.01E-05 CAU C22orf24 -1.1067551 1.28E-06 1.15E-05 CAU DIRAS2 -1.2388713 1.13E-06 1.04E-05 CAU INSRR -1.2520204 1.33E-06 1.19E-05 CAU HIGD1C 1.49013238 8.05E-07 7.92E-06 CAU LOC101928855 1.00892415 1.44E-06 1.27E-05 CAU DOK6 -1.0420068 1.15E-06 1.05E-05 CAU CDKN1A 1.15989632 1.17E-06 1.07E-05 CAU LINC02388 1.07114508 1.27E-06 1.14E-05 CAU HTR6 -1.7391627 1.47E-06 1.29E-05 CAU LOC101929613 1.33915192 1.16E-06 1.07E-05 CAU PLK2 -1.2115318 1.20E-06 1.09E-05 CAU CNTN6 -1.1624975 1.50E-06 1.31E-05 CAUPCDHGC5 -1.6323725 1.29E-06 1.16E-05 CAU SEMA3G -1.1371746 1.35E-06 1.20E-05 CAU DGKB -1.3080637 1.36E-06 1.21E-05 CAU CARNS1 -1.2869709 1.43E-06 1.26E-05 CAU HGFAC 1.43243955 1.72E-06 1.46E-05 CAU NUCB1-AS1 1.96782489 1.01E-06 9.54E-06 CAU LPL -1.3773246 1.42E-06 1.25E-05 CAU MYLK2 -1.3766361 1.75E-06 1.48E-05 CAU S100A4 1.06665774 1.88E-06 1.57E-05 CAU LOC100287944 -1.3785816 1.37E-06 1.22E-05 CAU SLC4A10 -1.1245252 1.58E-06 1.37E-05 CAU KRTAP5-7 -1.1789721 1.49E-06 1.31E-05 CAU MARCHF4 -1.2001547 1.71E-06 1.46E-05 CAU CCDC87 -1.1469306 1.74E-06 1.48E-05 CAU RIMBP2 -1.1213716 1.68E-06 1.44E-05 CAU G0S2 1.65651543 2.05E-06 1.67E-05 CAU TMEM150B 1.12478051 1.86E-06 1.56E-05 CAU CCKBR -1.3879399 2.04E-06 1.66E-05 CAU KNCN -1.5268804 1.65E-06 1.42E-05 CAU NEXN-AS1 1.06999644 2.00E-06 1.64E-05 CAU ATP11A-AS1 1.01149893 2.10E-06 1.70E-05 CAU LINC01133 1.18477929 2.00E-06 1.64E-05 CAU LTA 1.6302711 1.35E-06 1.20E-05 CAU RAB3A -1.2667783 1.78E-06 1.50E-05 CAU SLC23A3 1.10742328 1.91E-06 1.59E-05 CAU GABRD -1.3875088 1.82E-06 1.53E-05 CAU C9orf152 1.52161051 1.47E-06 1.29E-05 CAU MYOG 1.19412791 2.35E-06 1.87E-05 CAU CD96 1.07380634 2.49E-06 1.96E-05 CAU SNORD14E 1.94422503 1.86E-06 1.56E-05 CAU SMAD1-AS2 1.78095258 1.56E-06 1.36E-05 CAU RASGRP1 -1.0974389 2.01E-06 1.64E-05 CAU CALB2 -1.1770434 2.08E-06 1.69E-05 CAU LOC101929353 -1.7845441 2.15E-06 1.73E-05 CAU DRD3 -1.9564939 2.63E-06 2.04E-05 CAU MC4R -1.7721334 2.70E-06 2.09E-05 CAU HEATR9 1.23503632 2.52E-06 1.98E-05 CAU RNU6-1 1.51685142 2.80E-06 2.15E-05 CAU ADH1B 1.15750913 2.87E-06 2.20E-05 CAU FKBP5 1.08695673 2.19E-06 1.76E-05 CAU GACAT2 -1.535136 2.15E-06 1.73E-05 CAU CXCL1 1.67908451 2.81E-06 2.15E-05 CAUACTN2 -1.1707613 2.35E-06 1.87E-05 CAU OR2W3 -1.4595459 2.60E-06 2.03E-05 CAU LOC286177 1.05959912 2.69E-06 2.08E-05 CAU CCDC177 -1.1079897 3.39E-06 2.51E-05 CAU CLSTN3 -1.2082106 2.63E-06 2.04E-05 CAU GAD1 -1.4560174 2.61E-06 2.03E-05 CAU ANKRD63 -1.8415323 3.41E-06 2.52E-05 CAU SAP25 1.47342307 3.54E-06 2.59E-05 CAU UPK1A 1.67665444 2.38E-06 1.89E-05 CAU SYT4 -1.3747141 2.77E-06 2.13E-05 CAU GABRE 1.12241821 3.65E-06 2.64E-05 CAU OBSCN-AS1 -1.2108375 2.99E-06 2.27E-05 CAU SLCO4A1-AS1 1.78807504 3.02E-06 2.29E-05 CAU SST -1.5972735 2.94E-06 2.24E-05 CAU TRPC7 -1.4417756 3.11E-06 2.33E-05 CAU FLJ42393 1.02293308 3.93E-06 2.81E-05 CAU LINC01249 1.03875591 3.75E-06 2.71E-05 CAU RAB7B -1.0741874 4.02E-06 2.86E-05 CAU MIR202HG 1.01825816 3.81E-06 2.74E-05 CAU LOC100506071 -1.6782928 4.07E-06 2.89E-05 CAU ADAMTS9 1.29009566 3.48E-06 2.56E-05 CAU CX3CR1 -1.2790144 3.39E-06 2.51E-05 CAU ZCCHC12 -1.2271026 3.37E-06 2.50E-05 CAU PDE10A -1.4272442 3.25E-06 2.43E-05 CAU GLDN -1.0227893 3.26E-06 2.44E-05 CAU SLC35D3 -1.5289374 4.20E-06 2.97E-05 CAU BPESC1 1.28241176 3.59E-06 2.61E-05 CAU NPTN -1.0142754 3.49E-06 2.56E-05 CAU NMNAT2 -1.2146105 3.38E-06 2.50E-05 CAU WNT16 -1.5839283 4.37E-06 3.07E-05 CAU UNC5D -1.1463687 4.26E-06 3.00E-05 CAU SLC2A13 -1.0220848 3.46E-06 2.55E-05 CAU SUSD4 -1.0444309 3.59E-06 2.61E-05 CAU CRABP2 -1.06232 4.24E-06 2.99E-05 CAU PRSS56 -1.1788254 4.50E-06 3.13E-05 CAU NCEH1 -1.0433169 3.58E-06 2.61E-05 CAU TRH -1.4776822 4.87E-06 3.34E-05 CAU CYP2C8 -1.0610599 4.97E-06 3.39E-05 CAU VAT1L -1.5699736 3.95E-06 2.82E-05 CAU GOLT1A -1.210391 4.96E-06 3.38E-05 CAU MSX1 1.07177744 4.73E-06 3.26E-05 CAU CKMT1B -1.1775456 3.98E-06 2.84E-05 CAUKCNH1 -1.04242 4.20E-06 2.96E-05 CAU ZIM3 1.10347607 4.72E-06 3.26E-05 CAU TMEM200B -1.1109186 4.82E-06 3.31E-05 CAU TNFSF8 -1.0555776 4.65E-06 3.22E-05 CAU SULT4A1 -1.3636649 4.11E-06 2.91E-05 CAU LINC02185 1.39017984 4.77E-06 3.29E-05 CAU C6orf141 -1.6559773 5.22E-06 3.52E-05 CAU VCAM1 -1.0314435 5.45E-06 3.65E-05 CAU TEAD4 1.03073626 5.74E-06 3.80E-05 CAU PAQR9 -1.3733791 5.74E-06 3.80E-05 CAU TMEM171 -1.3795643 5.53E-06 3.70E-05 CAU RAB27B -1.2459396 5.62E-06 3.74E-05 CAU ST8SIA6-AS1 1.01094994 6.05E-06 3.98E-05 CAU CEACAM5 1.29455859 5.32E-06 3.58E-05 CAU PLA1A 1.39240876 6.34E-06 4.12E-05 CAU GABRA1 -1.1653455 5.07E-06 3.44E-05 CAU CIDEA -1.4556252 6.71E-06 4.31E-05 CAU TAGLN3 -1.2386748 5.13E-06 3.47E-05 CAU TNFRSF8 -1.6353158 6.57E-06 4.25E-05 CAU GABRG2 -1.2888942 5.14E-06 3.48E-05 CAU MCHR1 -1.330574 6.79E-06 4.36E-05 CAU CCDC196 -1.1471051 5.67E-06 3.77E-05 CAU ACRV1 -1.0830304 6.94E-06 4.42E-05 CAU SMIM32 -1.5548942 6.95E-06 4.43E-05 CAU IL4R 1.07953583 5.67E-06 3.77E-05 CAU LOC101927560 1.03290102 7.25E-06 4.58E-05 CAU INKA2-AS1 -1.0246239 7.09E-06 4.50E-05 CAU HOXB13 1.05044219 7.39E-06 4.65E-05 CAU TUBB1 1.05831346 6.19E-06 4.05E-05 CAU TMEM121B -1.1046497 6.08E-06 3.99E-05 CAU PMEL 1.25951384 5.70E-06 3.78E-05 CAU ENC1 -1.4954777 5.97E-06 3.94E-05 CAU HTR5A -1.374148 7.79E-06 4.85E-05 CAU SNAP25 -1.4149554 6.78E-06 4.35E-05 CAU RDH8 1.34762581 7.62E-06 4.77E-05 CAU CACNA1S -1.1811311 8.72E-06 5.31E-05 CAU NUDT11 -1.0552086 7.20E-06 4.56E-05 CAU CCNB3 -1.0386659 8.71E-06 5.30E-05 CAU LOC153910 1.28490615 6.93E-06 4.42E-05 CAU SLC12A3 1.32385897 8.40E-06 5.15E-05 CAU TTC39C-AS1 1.04075911 7.18E-06 4.55E-05 CAU ANGPTL4 1.0974189 6.76E-06 4.34E-05 CAUTGFB3 1.06257837 6.77E-06 4.35E-05 CAU BATF -1.1940587 9.34E-06 5.60E-05 CAU STRIP2 -1.2784539 6.98E-06 4.44E-05 CAU NMBR -1.3637384 8.37E-06 5.14E-05 CAU ADGRF2 1.00089261 9.52E-06 5.69E-05 CAU PABPC1L2B -1.1008627 9.43E-06 5.64E-05 CAU STX1B -1.0435214 7.54E-06 4.73E-05 CAU LINC00470 1.23169189 9.21E-06 5.55E-05 CAU KCNQ3 -1.0720827 7.50E-06 4.71E-05 CAU GPR139 -1.8970014 9.46E-06 5.66E-05 CAU LL22NC01- 1.20171895 1.04E-05 6.12E-05 CAU 81G9.3 PCSK2 -1.1285842 8.10E-06 5.01E-05 CAU NBPF14 1.03476661 8.32E-06 5.12E-05 CAU MAGEL2 -1.2840775 1.05E-05 6.18E-05 CAU CHGB -1.0950319 8.45E-06 5.17E-05 CAU SH2D5 -1.2501274 8.65E-06 5.28E-05 CAU VSTM2L -1.0224267 8.98E-06 5.44E-05 CAU SLC52A3 1.11654631 1.15E-05 6.63E-05 CAU SERPINC1 1.34461492 9.38E-06 5.62E-05 CAU RGS8 -1.4636455 9.73E-06 5.80E-05 CAU SGCG -1.0887649 1.18E-05 6.74E-05 CAU GRM5 -1.023897 9.85E-06 5.85E-05 CAU ZNF503-AS1 -1.0528305 1.33E-05 7.47E-05 CAU CNR1 -1.4412532 1.07E-05 6.24E-05 CAU MPZL2 1.14670282 1.46E-05 8.10E-05 CAU MT1G 1.27953012 1.06E-05 6.20E-05 CAU ANKRD34C- -1.0573421 1.52E-05 8.37E-05 CAU AS1 RAB3C -1.3375307 1.10E-05 6.39E-05 CAU LOC101928674 1.33201365 1.19E-05 6.78E-05 CAU CARNMT1- 1.09813981 1.55E-05 8.53E-05 CAU AS1 OPALIN -1.0068282 1.19E-05 6.80E-05 CAU TARM1 1.18145357 1.63E-05 8.87E-05 CAU GABRA3 -1.0331931 1.45E-05 8.06E-05 CAU LTB4R2 -1.0123552 1.58E-05 8.63E-05 CAU CDK5R2 -1.2690277 1.24E-05 7.03E-05 CAU GYS2 1.23531641 1.61E-05 8.80E-05 CAU IL6 1.85963348 1.54E-05 8.46E-05 CAU RGS7BP -1.1765048 1.41E-05 7.86E-05 CAU RPH3A -1.0976736 1.40E-05 7.79E-05 CAU C19orf33 1.08852563 1.88E-05 0.00010049 CAU ZNF664- -1.03267 2.08E-05 0.00010931 CAU RFLNAHTR1E -1.2206594 2.11E-05 0.0001104 CAU TMEM265 1.20965444 2.14E-05 0.00011156 CAU ACPP 1.06368212 2.20E-05 0.00011402 CAU FSTL4 -1.1507026 1.75E-05 9.45E-05 CAU SLC32A1 -1.5003718 1.66E-05 9.02E-05 CAU ORM2 1.07434494 1.88E-05 0.00010058 CAU ARHGAP40 -1.2783681 2.36E-05 0.00012142 CAU KCNS2 -1.2999923 2.34E-05 0.00012027 CAU PLCXD2 -1.2591831 2.21E-05 0.00011469 CAU HTR2C -1.4755736 1.83E-05 9.81E-05 CAU SLC1A7 1.64774285 2.57E-05 0.00012998 CAU IZUMO1 1.20595762 2.39E-05 0.00012238 CAU FAM9A 1.11138543 2.63E-05 0.00013223 CAU ACTL6B -1.0869445 1.91E-05 0.0001019 CAU SERPINE1 1.12266422 2.51E-05 0.00012721 CAU RIMBP3C -1.6148687 2.70E-05 0.0001352 CAU STC1 1.1786568 2.70E-05 0.00013505 CAU LINC00460 -1.2548808 2.80E-05 0.00013974 CAU SEZ6 -1.190235 2.01E-05 0.00010647 CAU MMP23B 1.57612455 2.50E-05 0.00012717 CAU WASIR2 1.15994853 2.86E-05 0.00014192 CAU GLP1R -1.3499252 2.93E-05 0.00014502 CAU UNC13A -1.0465502 2.13E-05 0.00011133 CAU MIR8082 1.22838206 2.54E-05 0.00012858 CAU SLC12A5 -1.2529399 2.14E-05 0.00011166 CAU ENTPD3 -1.3558848 2.15E-05 0.00011217 CAU CRYBA1 1.2880437 2.32E-05 0.00011961 CAU CAP2 -1.0287552 2.10E-05 0.00011008 CAU DLGAP2 -1.0769909 2.19E-05 0.00011397 CAU LRTM2 -1.3769531 2.19E-05 0.00011395 CAU SH3GL2 -1.0919294 2.21E-05 0.00011466 CAU PDE1B -1.3898727 2.44E-05 0.00012432 CAU GPR55 -1.296013 3.20E-05 0.0001562 CAU SFTPA2 -1.2463851 2.99E-05 0.00014744 CAU ZNF341-AS1 1.26298288 2.63E-05 0.00013254 CAU GOLGA8F 1.91820875 2.71E-05 0.0001359 CAU UNC5A -1.0474731 2.55E-05 0.00012907 CAU VIT -1.1080841 3.60E-05 0.00017224 CAU NGEF -1.385655 2.76E-05 0.00013766 CAU FOXN4 1.412332 2.99E-05 0.00014763 CAU ABCC5-AS1 1.23401933 3.63E-05 0.00017375 CAU CALY -1.0849825 2.72E-05 0.00013628 CAULINC00159 1.09939894 3.41E-05 0.00016483 CAU LOC100130548 1.05993293 3.96E-05 0.00018758 CAU GLS2 -1.0444106 3.11E-05 0.00015223 CAU STC2 1.08263579 4.22E-05 0.00019785 CAU MIR3945HG 1.08515213 4.46E-05 0.00020749 CAU SNORD63 1.31062818 4.01E-05 0.00018953 CAU LINC01123 -1.1338141 3.79E-05 0.00018073 CAU CENPVL1 -1.1253326 4.50E-05 0.00020917 CAU GPR149 -1.2826967 4.65E-05 0.00021493 CAU PAK6 -1.0301118 3.32E-05 0.00016135 CAU RCVRN 1.06861835 4.97E-05 0.00022658 CAU ACHE -1.0295192 3.51E-05 0.00016875 CAU TMEM130 -1.0067354 3.80E-05 0.0001813 CAU MT1H 1.44459416 4.75E-05 0.00021884 CAU LOC105369509 1.03254909 5.45E-05 0.00024498 CAU FAM163B -1.030451 4.94E-05 0.00022568 CAU BCL2A1 1.55000793 5.33E-05 0.00024059 CAU LOC101929054 1.13734517 5.07E-05 0.00023062 CAU ARPP21 -1.2026062 4.51E-05 0.00020932 CAU NMUR2 1.35808534 5.83E-05 0.00025933 CAU NLRP8 1.08985962 5.66E-05 0.00025323 CAU CRYGD -1.2200111 5.49E-05 0.00024627 CAU LINC02192 -1.1173473 6.00E-05 0.00026618 CAU SNX31 1.28874448 5.91E-05 0.00026255 CAU CDHR1 -1.0505203 4.08E-05 0.00019258 CAU LIN28B-AS1 -1.0594999 5.81E-05 0.00025875 CAU WT1 -1.3199617 6.50E-05 0.00028423 CAU WSCD2 -1.1317615 4.41E-05 0.00020579 CAU NSG2 -1.2549118 5.06E-05 0.00023048 CAU GPR158-AS1 -1.0055112 7.10E-05 0.00030603 CAU C9orf129 -1.0286171 7.31E-05 0.00031322 CAU LOC101927166 1.01820213 7.26E-05 0.00031147 CAU SERPINE3 -1.1623035 7.11E-05 0.00030624 CAU LINC00930 1.25083829 7.12E-05 0.00030625 CAU EGR3 -1.0963912 5.72E-05 0.00025525 CAU MARCHF11 -1.0348747 8.97E-05 0.00037311 CAU LOC100129603 1.48166814 8.56E-05 0.00035869 CAU DACT2 -1.0492521 6.48E-05 0.00028359 CAU LINC00484 1.14769934 8.41E-05 0.00035341 CAU ST6GALNAC5 -1.105182 7.90E-05 0.00033429 CAU BIVM-ERCC5 -3.0744178 8.67E-05 0.00036274 CAU LOC102723831 1.21699913 8.77E-05 0.00036618 CAUCPLX2 -1.1448065 7.38E-05 0.00031596 CAU LOC100505795 1.14140394 9.86E-05 0.00040363 CAU PCP4L1 -1.384255 6.60E-05 0.00028752 CAU MIR3663HG 1.17106601 0.00010008 0.00040895 CAU CELSR1 1.06428976 9.20E-05 0.00038127 CAU LOC105369507 1.28562384 9.69E-05 0.00039795 CAU ATP1A3 -1.2689489 7.68E-05 0.00032648 CAU SLAMF8 1.06139301 0.00011481 0.00045652 CAU PEX5L-AS2 1.2167796 0.00011439 0.00045532 CAU SPATA46 1.27675357 0.00010715 0.00043245 CAU ST8SIA3 -1.3094282 7.97E-05 0.00033715 CAU SNORD115-45 -1.1550526 0.00011879 0.00046908 CAU FBXL16 -1.1300729 9.61E-05 0.00039511 CAU SH2D1A 1.06233616 0.00011984 0.00047213 CAU ERI3-IT1 1.13985903 0.00012392 0.00048539 CAU SYCE3 -1.1963796 0.00011698 0.00046338 CAU SLC6A17 -1.0040071 8.30E-05 0.00034988 CAU HIPK4 -1.2562773 9.07E-05 0.00037651 CAU HGD 1.22149755 0.0001389 0.00053526 CAU CRYM -1.3276017 8.92E-05 0.00037174 CAU FAT2 -1.2198764 0.00011536 0.00045802 CAU CNGA3 -1.3921617 0.00014066 0.00054082 CAU NPB -1.5207221 0.00013792 0.00053189 CAU ICAM5 -1.2804812 0.00010214 0.00041605 CAU IL1R2 1.83961661 0.00014182 0.00054441 CAU RPRML -1.1092299 0.00012791 0.00049867 CAU OR2L2 -1.256943 0.00014785 0.00056354 CAU POU4F1 1.04037011 0.00016072 0.00060436 CAU RGS14 -1.3462783 0.00011525 0.00045785 CAU RASD2 -1.2429516 0.00012429 0.00048675 CAU PALM2AKAP2 -1.0159226 0.00014152 0.00054345 CAU ADCYAP1 -1.2151999 0.00017371 0.00064477 CAU INA -1.0738696 0.00011964 0.00047166 CAU CHRM1 -1.2213843 0.0001229 0.00048211 CAU RGS4 -1.0124025 0.00012525 0.00049011 CAU HES5 -1.112659 0.00019143 0.00070181 CAU TMIE 1.06554873 0.00017306 0.00064273 CAU KCNQ5 -1.2117232 0.00013463 0.00052081 CAU CHRM4 -1.4714405 0.00015971 0.00060128 CAU LINC01679 1.1212239 0.0002171 0.00078154 CAU ANO3 -1.4778034 0.00014783 0.00056354 CAU KCNG3 -1.0360008 0.00021712 0.00078154 CAUHTR1A -1.4361981 0.00021944 0.00078802 CAU NCDN -1.0898893 0.00017679 0.00065466 CAU EEF1A2 -1.0057187 0.0001689 0.00062965 CAU CCL19 -1.6287956 0.00026445 0.00092227 CAU CORT -1.0730331 0.00017895 0.00066203 CAU FITM1 1.09988715 0.00027645 0.00095848 CAU CBLN4 -1.3164965 0.00026712 0.00093052 CAU MME -1.1884402 0.00018989 0.00069707 CAU HBA2 -1.5561936 0.00018826 0.00069177 CAU SCG2 -1.0788977 0.00019327 0.00070688 CAU KCNC2 -1.2687247 0.00024844 0.00087495 CAU NPY -1.2510823 0.00019246 0.00070472 CAU ELOA2 1.0509959 0.00030849 0.00105039 CAU PCDH8 -1.19974 0.00020076 0.00073037 CAU C16orf90 1.29974763 0.00028903 0.00099503 CAU FNDC7 -1.0946129 0.00031623 0.0010731 CAU TPBG -1.0037044 0.00019904 0.00072476 CAU LOC401442 -1.0409753 0.0003227 0.00109057 CAU OR1F1 -1.1978149 0.00033756 0.0011327 CAU IL13RA2 -1.0637108 0.00032057 0.00108491 CAU RBPMS-AS1 1.00496927 0.00033074 0.00111298 CAU ADAMTS9- 1.2093474 0.00035156 0.00117224 CAU AS1 LOC101928663 1.1218807 0.00033358 0.00112096 CAU LOC100130238 1.82968026 0.00032497 0.00109666 CAU CAMK4 -1.0043905 0.0002217 0.00079478 CAU HBB -1.6784583 0.00023139 0.00082518 CAU TUNAR -1.0451704 0.00022815 0.00081502 CAU LCN6 1.29363726 0.00035832 0.00119073 CAU SERTM1 -1.1858994 0.00038401 0.00126321 CAU GOLGA8K -1.4797663 0.00040479 0.00131981 CAU CD164L2 -1.5114907 0.00036785 0.0012182 CAU RNF216-IT1 1.08960401 0.00041679 0.00135292 CAU ACTN3 1.01628528 0.00043463 0.00140218 CAU H4C4 1.56102064 0.00042306 0.00137 CAU HOXD1 -1.0755517 0.00045664 0.00146376 CAU CACNG3 -1.1093693 0.00028709 0.00098941 CAU GFRAL 1.04166666 0.00047481 0.00151324 CAU NRGN -1.0562998 0.00036837 0.00121972 CAU SLC17A4 1.09907199 0.00055015 0.00171542 CAU ITPKB-IT1 1.03558793 0.00054867 0.00171109 CAU CLDN19 1.33712405 0.00053627 0.00167737 CAU LAMP5 -1.1822439 0.00035036 0.00116988 CAUTESPA1 -1.1027656 0.00035093 0.00117139 CAU S100A8 1.6365421 0.00054779 0.00170907 CAU L1CAM -1.0791065 0.00035678 0.00118678 CAU TAC1 -1.3622852 0.00036848 0.00121988 CAU SYN2 -1.0985078 0.00037773 0.0012457 CAU PAX7 -1.0541185 0.00065277 0.001989 CAU GOLGA8G -1.1612729 0.00060785 0.00187195 CAU CAMKV -1.0690172 0.00040629 0.00132405 CAU CSF3 1.97211171 0.00070384 0.0021258 CAU NNAT -1.0363575 0.00045736 0.00146581 CAU HPCA -1.1705612 0.00052024 0.0016364 CAU SENP3-EIF4A1 1.87813696 0.000819 0.00243037 CAU RPEL1 -1.0205802 0.00089867 0.00263589 CAU AMIGO3 1.90383476 0.00096041 0.00279239 CAU PENK -1.5891161 0.00056785 0.00176481 CAU SYNPR -1.1642522 0.00057922 0.00179516 CAU KCNJ1 -1.0305743 0.00092794 0.00271045 CAU CCL2 1.01489865 0.00082581 0.00244599 CAU RAI1-AS1 1.07931247 0.00105459 0.00302681 CAU AGXT 1.09039157 0.00110354 0.00314685 CAU WNT1 -1.1449829 0.00110404 0.00314781 CAU GAD2 -1.1327383 0.00064009 0.00195635 CAU NMRK2 1.31203396 0.0011363 0.00322768 CAU MACROD2- 1.02933318 0.00121012 0.00340626 CAU IT1 HBA1 -1.4192984 0.00068454 0.00207615 CAU IL1RL1 1.57847864 0.00095114 0.00276885 CAU ZBTB20-AS5 1.03684017 0.00139866 0.00385302 CAU TMEM238L 1.06334137 0.00140753 0.00387238 CAU SOST 1.218272 0.00145956 0.00399584 CAU TACSTD2 -1.0721827 0.00157224 0.00426376 CAU S100A12 1.76402933 0.00167242 0.00449498 CAU MUC5B -1.0350918 0.00165652 0.00445856 CAU CCDC168 1.39601231 0.0016926 0.00454087 CAU COL18A1-AS1 1.19995964 0.00171841 0.00460095 CAU SV2C -1.0037233 0.00100816 0.00291182 CAU SERPINA5 1.15443696 0.00160839 0.00434689 CAU TPSD1 1.22370102 0.0019742 0.00519483 CAU MYO1A -1.0308659 0.00225469 0.00582019 CAU GOLGA8T -1.4908941 0.002321 0.00595331 CAU RIMBP3B -1.6346635 0.00233361 0.00598234 CAU PDYN -1.3675448 0.00132831 0.0036935 CAU TNFRSF11B 1.03150705 0.00235303 0.00602327 CAUMIR4451 1.09386869 0.00258387 0.00652792 CAU NBPF4 -1.4787735 0.00262025 0.0066014 CAU COCH -1.1418459 0.00150226 0.00409621 CAU RIMBP3 -1.0764797 0.00289278 0.00717375 CAU NPAS4 -1.3002429 0.00302544 0.00745115 CAU SERPINA3 1.0946679 0.00172096 0.00460654 CAU S100A9 1.33880775 0.0026704 0.00670639 CAU PTPRCAP -1.4471546 0.00378313 0.00902344 CAU CCL3L3 -1.0665697 0.00390353 0.00926521 CAU HSPE1-MOB4 1.71285897 0.0037657 0.00898654 CAU TVP23C- -1.4155948 0.00402418 0.00950523 CAU CDRT4 DOK2 1.17803577 0.00429408 0.0100651 CAU KCNJ4 -1.0095985 0.00212016 0.00552854 CAU GPR6 -1.0644304 0.00234163 0.00599975 CAU OR7C1 1.14040165 0.00494909 0.01140888 CAU POTEH 1.2567446 0.00618423 0.01382965 CAU OR7A5 1.37627383 0.00718455 0.01574036 CAU MAGI2-AS2 1.00616205 0.00802944 0.01731984 CAU CD177 1.20133495 0.00802563 0.0173153 CAU SNORD86 1.03215997 0.00673029 0.01487732 CAU CT45A1 -1.3543361 0.00881276 0.01876405 CAU PAPPA-AS1 1.32097019 0.01059187 0.02202115 CAU PVALB -1.0319574 0.00843601 0.01806317 CAU ELOA3B 1.1124134 0.01025374 0.02140018 CAU C6 -1.1339739 0.01277025 0.0257932 CAU TNFRSF6B 2.03044702 0.01224326 0.02490096 CAU HSFY2 -1.1230483 0.01744328 0.03366547 CAU ZFP91-CNTF 1.54159129 0.02229519 0.04155843 CAU [000212] To assess the value of RNA-seq in the prediction of clinical diagnosis, we undertook a machine learning approach to identify binary classifier genes that can distinguish PD from controls. Using a group of 70% of control and donor PD caudates as a training dataset, we identified a set of 19 classifier genes which identified clinical diagnosis with 86% accuracy (TABLE 5A). The same set of classifier genes predicted clinical diagnosis in the putamen with 90% accuracy (Fig 1g, TABLE 5B). TABLE 5A Gene ANGPT2 ANGPT4 TRIP10 DEPP1 ANKRD20A2MYBPC1 LINC01338 MT1M NUPR1 VGF TUBB3 CIRBP TARBP1 HBA2 HBA1 HBB LBH GPCPD1 SEMA3G TABLE 5B Satistics for Caudate trained classifier Accuracy : 0.8654 95% CI : (0.7421, 0.9441) No Information Rate : 0.5577 P-Value [Acc > NIR] : 2.105E-06 Kappa : 0.7259 Mcnemar's Test P-Value : 1 Sensitivity : 0.8966 Specificity : 0.8261 Pos Pred Value : 0.8667 Neg Pred Value : 0.8636 Prevalence : 0.5577 Detection Rate : 0.5 Detection Prevalence : 0.5769 Balanced Accuracy : 0.8613 Accuracy of classifier on putamen PD and 0.9067 Control samples. [000213] The majority of PD donors were on dopaminergic medications. To examine whether transcriptional changes identified were impacted by medication, we tested the effect of levodopaequivalent drug dose (LEDD)36in our differential gene expression model, allowing the identification of RNAs associated with PD independent of their association with drug dose. This analysis showed that >95% of RNAs were significantly up and downregulated in PD independent of drug dose (Fig 2e), and a high correlation (r = 0.98, p < 2.2e-16) was seen for differentially changed pathways in PD before and after accounting for the effect of drug dose (Fig 2f). These results indicate that drug dose did not make a detectable difference on the transcriptome in postmortem brains. [000214] Mass spectrometry on brain samples (PD caudate (n=10), PD putamen (n=12) and control (n=5)) confirmed a correlation between expression levels of RNA and protein in the striatum (Fig 3a,c, data not shown). GO terms altered in the RNA-seq were similarly affected at the protein level (Fig 3b,d, data not shown). The mitochondrial proteome was the most downregulated term in caudate (including proteins involved in mitochondrial envelope, mitochondrial protein complex, and mitochondrial gene expression), along with ion transport and lipid metabolic processes, while immune-mediated GO terms were upregulated (Fig 5b). In putamen, transmembrane transport, lipid metabolism, and mitochondrial envelope terms were downregulated, while inflammatory pathways were upregulated (Fig 3d), consistent with RNA-seq. These results provide independent support for the findings seen by RNA-seq, indicating that the RNA changes give rise to steady-state protein changes in PD striatum. [000215] Concordant Transcriptome Chanes in Brain and Peripheral Blood Peripheral blood transcriptome studies in Alzheimer’s disease have reported findings that mirror brain pathology23,24. Therefore, we tested whether the transcriptional changes we identified in PD caudate and putamen were also altered in antemortem blood collected from PD patients (n=479) compared to control donors (n=195) in the PPMI cohort (TABLE 6 and data not shown). About 1015 and 569 RNAs were significantly up or downregulated in PD blood (Fig 4a and data not shown), consistent with prior analysis of this data27. Remarkably, we observed that mRNAs significantly up or downregulated in the PD caudate and putamen were altered in the same direction in the blood (Fig 4b, Fig 5a). TABLE 6 Controls (n=195) PD p value Test (n=479) Age at collection (years) 60.8 (11.3) 61.6 (9.8) 0.572 Wilcoxon Male / Female 125 / 70 311 / 168 0.860 (gender) Fisher test Race (White / Black / Hispanic / Other) 180 / 10 / 1 / 4 444 / 7 / 9 / 19 1 Fisher test Age of onset / diagnosis (years) NA 59.6 (10.1) NA Disease duration (years) NA 6.8 (6.7) NA quality (% usable bases) 41.0 (8.4) 41.1 (9.4) 0.589 Wilcoxon Mean (standard deviation); p values were determined using listed tests[000216] To confirm this observation, we analyzed blood bulk RNA-seq data from an independent cohort, the Parkinson’s Disease Biomarker Program (PDBP). There was a significant correlation between differentially expressed PD RNAs detected in the PPMI and PDBP cohorts. Cumulative changes in RNAs significantly up or downregulated in the PD brain were changed in the same direction in the PDBP blood (data not shown). While the evaluation of a large number (>5000) of significant striatal PD associated RNAs in the blood expectedly limit the overall effect size in blood, these findings indicate consistent concordance between postmortem brain and antemortem blood RNAs in PD. [000217] For example, SNCA, which encodes alpha-synuclein and is linked to a familial form of PD37,38, was significantly downregulated in both the blood and brain, consistent with smaller targeted RNA studies in the blood and with prior analysis of PPMI data (Fig 4a,c)27,39. TOMM70, an import receptor involved in the import of PINK-1 into the mitochondria40, was also significantly downregulated in PD caudate, putamen, and blood (Fig 4a,c) as was the calcium-dependent kinase CAMK4 (Fig 4a). Upregulated RNAs discovered in both the blood and the brain were immune pathway genes including (FCAR (Fig 4a,c), IL1R2), stress induced molecular chaperone HSPA6 and genes important in brain function such as the G protein coupled receptor PROK2 and neuronal acetyl cholinergic receptor CHRNA10 (Fig 4a). [000218] Significant changed (up- and downregulated) GO terms detected in the PD caudate and putamen were also collectively consistent in their direction of change in PD peripheral blood (Fig 5b, data not shown). Similar to our observations of RNA changes in PD caudate and putamen, transcripts encoding proteins in miRNA regulation and immune response (Toll-like receptor signaling, interleukin secretion and NF kappa B signaling) were upregulated in the blood (Fig 4d). Conversely, and again consistent with observations in the PD caudate and putamen, where we observed downregulation of neuronal and synaptic pathways, GO terms downregulated in PD blood included postsynaptic membrane, glutamine metabolic process and neuron maturation (Fig 4d). Direction of change in top differentially changed GO terms in PD blood were driven by changes in most genes in the GO term (Fig 5c). [000219] The top GO terms identified as dysregulated in GSVA of PD blood were neuronal, such as “extrinsic component of postsynaptic specialization / density membrane” and interestingly, inversely correlated with motor progression, based on two different clinical scales (Movement disorders society (MDS)-unified Parkinson’s disease rating score (UPDRS) and modified Hoehn and Yahr scale)41,42(Fig 4e). Similarly, TIAM-1, a gene in the postsynaptic membrane GO term encoding a known modulator of glutamatergic synapse function,43,44was significantly decreased in PD caudate, putamen, and blood, and its expression inversely correlated with motor severity in the PPMI cohort (Fig 5d). Peripheral blood from antemortem PD subjects shows concordant changes in RNA expression with PD brain, and strikingly, these antemortem blood signatures correlate with PD progression.[000220] We also observed concordance between the blood of prodromal subjects27who were not clinically diagnosed with PD, but had clinical signs suggesting risk for PD (n=60) (such as anosmia, sleep disorder, and dopamine transporter scan showing loss of dopamine) and postmortem PD caudate (Figure 5e). In contrast, compared to controls, carriers of PD-related genetic mutations who were otherwise healthy, did not show concordance with the direction of change in PD brain RNA (Figure 5e, data not shown) suggesting that such concordance is detectable in the blood when pathology has also manifested in the brain. [000221] We next investigated if blood transcriptome changes seen in PD blood were influenced by medication use and found that about 40% (619 and 506 (38% and 43%) of previously identified up- and down-regulated RNAs) in PD blood changed independent of medication dose (LEDD), suggesting a greater effect of medications on the blood compared to the brain transcriptome (Fig 6a). The concordance between the blood and brain transcriptome remained true with differentially expressed RNAs and pathways independent of medication dose in PD patients (Fig 6b,c). [000222] To further investigate the concordance between blood and brain in PD, we analyzed blood transcriptome changes in PD subjects when they were drug-naïve for dopaminergic medications. As expected, drug-naive PD subjects had lower MDS-UPDRS scores compared to those on medications (p value < 2.2 e-16) (Fig 6d). While this makes a complete uncoupling of the effect of medication and disease challenging, we nonetheless compared the transcriptome profile of drug-naive PD subjects to controls. This revealed that 34 and 17% of up- and downregulated RNAs in drug-naive PD blood were also seen in the PD striatum (Fig 6e, data not shown). For example, SNCA and FCAR were significantly down- and upregulated in PD blood even in drug-naive PD subjects (Figure 6f,g). Similarly, RNAs downregulated in the brain such as the neuronal enriched gene GPR52 and the PD gene DNAJC6 were also downregulated in PD blood in drug-naive patients (Figure 6f,g). In GSVA, differentially changed pathways showed significant correlation between drug-naive and PD subjects on dopaminergic medications (Fig 6h, data not shown). [000223] These observations were supported with data from an independent analysis that used machine learning to determine RNAs / genes that serve as classifiers to distinguish controls and PD among early stage (average disease duration of 2 years) drug-naive PPMI subjects45. We observed that up- and downregulated classifier RNAs / genes in the blood from early-stage drug-naive PPMI subjects were collectively changed in the same direction in the postmortem striatum, indicating that the PD blood transcriptome reflects changes in the PD brain independent of medication status (Figure 6i). [000224] Clinical-Molecular Analyis: Cognitive and Motor Complications [000225] As disease or pathology in the caudate, but not putamen, is associated with Parkinson’s disease dementia (PDD)13–16,46–48, we next assessed whether RNAs changed in PDD did so in a region- specific manner. Sixteen donors had a diagnosis of PDD and 11 had PD without dementia (see methods, TABLE 7A and TABLE 7B). Differential gene expression analysis in caudate identified 57 RNAs that were significantly changed in PDD compared to PD without dementia, while only 8 RNAswere significantly affected in the putamen (Fig 7a, Fig 8a, TABLE 8A and TABLE 8B, data not shown) TABLE 7A Cholinesterase Donor Sample ID Dementia Inhibitor Cognitive Test 1 2653_PD_CAU + + 2 2689_PD_CAU + + 3 2778_PD_CAU + + 4 2780_PD_CAU + - 23 / 30(MOCA) 5 2782_PD_CAU + + 6 2784_PD_CAU + + 7 2786_PD_CAU + + 8 2579_PD_CAU + + 9 2581_PD_CAU + + 10 2583_PD_CAU + + 11 2585_PD_CAU + - <25(BCAT) 12 2593_PD_CAU + + 13 2627_PD_CAU + + 14 2633_PD_CAU + + 15 2645_PD_CAU + + 16 2681_PD_CAU + - 9 / 30 (MMSE) 17 2679_PD_CAU - - 18 2685_PD_CAU - - 19 2725_PD_CAU - - 20 2727_PD_CAU - - 30 / 30 (6 YPTD); 27 / 30 (2 21 2788_PD_CAU - + YPTD) 22 2792_PD_CAU - - 24 2649_PD_CAU - - 25 2713_PD_CAU - - 26 2687_PD_Cau - - 27 2803_PD_Cau - - MOCA: Montreal Cognitive Assessment; BCAT: Brief Cognitive Assessment Tool ; MMSE: Mini Mental State Examination; YPTD: Years prior to death TABLE 7B p value p value (PDD p value Control PD-ND (PDD vs vs (PD-ND vs (n=40) (n=16) PDD (n=11) PD-ND) CTRL) CTRL) Test Age of death 72.4 (years) (11.8) 78.3 (8.3) 76.4 (6.5) 0.57 0.102 0.09 Wilcoxon Male / Fe 28 / 12 8 / 3 15 / 1 0.273 0.082 1 Fishermale Race (White / B lack / 9 Hispanic / (White) / 2 Other) 34 / 2 / 2 / 2 (Black) 16 (White) 0.157 1 0.368 Fisher Age of onset / dia gnosis (years) NA 64.3 (9.1) 63.1 (10.1) 0.937 NA NA Wilcoxon Disease duration (years) NA 12.9 (6.9) 13.4 (7.2) 1 NA NA Wilcoxon PMI 16.9 (hours) (7.6) 18.7 (8.9) 20.6 (10.1) 0.786 0.253 0.614 Wilcoxon RIN 6.6 (1.8) 4.7 (2.2) 6.1 (2.0) 0.103 0.332 0.011 Wilcoxon Mean (standard deviation); p values were calculated using listed tests TABLE 8A – Caudate RNAs PD with Dementia vs PD no dementia ID logFC AveExpr t P.Value adj.P.Val B MARS1 0.60744456 5.71126183 4.79923606 4.26E-06 0.01450274 4.01474854 CASTOR3 -0.712228 6.6820274 -4.7745573 4.73E-06 0.01450274 3.91234495 TRAPPC6A -0.6560987 3.32147778 -4.7475176 5.30E-06 0.01450274 3.7470222 C14orf132 -0.6508011 7.80910733 -4.724178 5.85E-06 0.01450274 3.69941551 NFAT5 0.46532267 6.62572179 4.66203775 7.59E-06 0.01660117 3.48610746 LONRF3 0.9560924 1.58521707 4.75930871 5.04E-06 0.01450274 3.36855065 PPP1R15B 0.58522026 5.17089954 4.62291439 8.93E-06 0.01758013 3.34341385 LINC01877 -1.0818691 0.94966666 -4.7224575 5.89E-06 0.01450274 3.05251952 CEBPG 0.78815121 5.02103858 4.5216655 1.35E-05 0.02202875 2.96516789 HMGXB4 -0.5463224 4.80053118 -4.5042428 1.45E-05 0.02202875 2.90051006 LOC102724919 1.42800659 -0.6433406 4.9950616 1.83E-06 0.01450274 2.85513347 ZKSCAN1 -0.6034133 7.21631369 -4.4776537 1.62E-05 0.02243354 2.79632457 NUCKS1 -0.5209112 9.00305593 -4.4576825 1.76E-05 0.02243354 2.68805275 E2F1 -0.6807049 3.41647074 -4.4486208 1.82E-05 0.02243354 2.65721951 SEL1L3 1.02266679 3.79957717 4.41095003 2.12E-05 0.02383677 2.5436886 SLCO1A2 -1.3099174 7.21104272 -4.4043455 2.18E-05 0.02383677 2.53121173 LOC101928988 -2.0393905 -0.9552996 -4.8619831 3.26E-06 0.01450274 2.41780112 GPN1 0.57005302 4.04561116 4.37278446 2.47E-05 0.02403883 2.41290815 CAPN2 0.58887577 6.56503369 4.36416719 2.56E-05 0.02403883 2.38943077 PELP1 -0.6262557 6.81460873 -4.3637487 2.56E-05 0.02403883 2.38736322 SH3GL3 -0.8214278 5.8941781 -4.2426962 4.14E-05 0.03544413 1.9570154 NFATC2IP -0.4318268 5.06137401 -4.2349315 4.27E-05 0.03544413 1.92954964 STAG3 -0.4153983 5.32406042 -4.2233861 4.46E-05 0.03544413 1.88869317 PPTC7 0.60870879 4.45163217 4.20701469 4.76E-05 0.03544413 1.83172335 ASPA -1.0069406 6.47734212 -4.1962823 4.96E-05 0.03544413 1.79426834CHCHD3 0.40924845 4.23098657 4.17813814 5.32E-05 0.03544413 1.73063004 CHAF1A -0.7618758 3.51573504 -4.1719803 5.45E-05 0.03544413 1.69364892 ZEB2 -1.0855978 8.28960265 -4.1669305 5.56E-05 0.03544413 1.68604401 PPP1R14A -1.3770837 5.77903764 -4.1583959 5.74E-05 0.03544413 1.66171434 SNX22 -0.8712326 5.14751566 -4.1523828 5.88E-05 0.03544413 1.64060021 PRKAR2A- -0.7032957 2.44541259 -4.1775972 5.33E-05 0.03544413 1.62238375 AS1 CCT5 0.70272699 6.00526711 4.14012272 6.16E-05 0.03544413 1.59842024 HPS3 0.51807594 3.4876199 4.13834263 6.21E-05 0.03544413 1.57903802 TARS1 0.5953144 5.01697074 4.13451477 6.30E-05 0.03544413 1.57890837 ADNP2 0.51063212 4.13373246 4.12350976 6.57E-05 0.03594991 1.5418217 USPL1 0.66991932 3.6944604 4.08496296 7.62E-05 0.04025491 1.40502055 FEM1C 0.43509141 5.30215835 4.07986139 7.77E-05 0.04025491 1.38982736 CTNNA3 -1.5165129 5.55512107 -4.0724038 7.99E-05 0.04027975 1.36479016 CDK19 -0.611942 6.53063501 -4.0658259 8.19E-05 0.04027975 1.34387312 TKT 0.65364636 7.39491862 4.059754 8.39E-05 0.04027975 1.32475828 OPALIN -1.4218243 7.28926452 -4.0514273 8.65E-05 0.04050548 1.29650138 NUFIP2 0.53180401 6.20989104 4.04574517 8.84E-05 0.04050548 1.2744754 PAAF1 -0.5558087 6.22328603 -4.0172671 9.85E-05 0.04368067 1.17769032 PDIA6 0.50145528 6.17759513 4.0099209 0.00010127 0.04368067 1.15297171 PMF1 -0.5026964 4.09006269 -3.9975315 0.00010611 0.04368067 1.11521709 LINC01184 -0.4009313 4.63561065 -3.9977513 0.00010602 0.04368067 1.11332392 GPAT2 -0.6991166 4.27274572 -3.9909265 0.00010878 0.04368067 1.0923702 SLFN5 -0.5913748 3.78795086 -3.9870038 0.00011039 0.04368067 1.07944514 PPP1R3D 0.87004131 3.24067526 3.97425478 0.0001158 0.04386005 1.02098469 GDE1 -0.4614452 6.78115324 -3.9642255 0.00012023 0.04388068 1.00171507 FDX1 0.40307284 3.81325345 3.95931496 0.00012246 0.04388068 0.98784974 ARFRP1 -0.3571693 5.3778306 -3.9591451 0.00012254 0.04388068 0.9802318 BMP6 1.1077522 2.13809625 3.98334145 0.00011192 0.04368067 0.93186408 SEPTIN4 -1.0953513 9.26618715 -3.9430607 0.00013012 0.04576413 0.92659785 ALG2 0.51396139 3.54985225 3.91968217 0.00014195 0.04904682 0.85572306 DLEU2L 0.99280193 0.71213594 3.98052543 0.00011311 0.04368067 0.63102619 LOC101927948 -2.4360854 -2.7342493 -4.5359149 1.28E-05 0.02202875 0.34812049 TABLE 8B - Putamen RNAs PD with Dementia vs PD no dementia ID logFC AveExpr t P.Value adj.P.Val B RGPD5 2.43876079 4.81475803 5.47965882 2.09E-07 0.00319478 6.79668888 TMEM150 -0.7827441 4.59432488 -5.3840176 3.24E-07 0.00319478 6.40884408 C GPAT2 -0.8628188 4.27274572 -4.8997423 2.77E-06 0.01819607 4.42232664 BTN2A2 0.82521742 3.03418089 4.76280484 4.97E-06 0.02446972 3.83840579 PDE1A -2.1598392 2.90476462 -4.5554336 1.18E-05 0.04392461 3.07825709 SYTL2 -1.2717885 3.61843354 -4.4867841 1.56E-05 0.04392461 2.83865727BMP6 1.2011059 2.13809625 4.4941924 1.51E-05 0.04392461 2.77711075 PELO 0.51316031 3.84680792 4.44887854 1.82E-05 0.04482033 2.69897696 [000226] GSVA identified more than 300 GO terms that were significantly changed in PDD compared to PD caudate (Fig 7b, Fig 8b, data not shown). Interestingly, no significant GO terms were identified in the putamen in the same patients, suggesting that the region-specific changes seen in the caudate are specifically linked to dementia (Fig 8b). Significant GO terms in PDD caudate included circadian regulation of gene expression and stress response pathways, including protein kinase C signaling, histone H4 acetylation, mitochondrial DNA metabolic process (Fig 7b,c). [000227] We next assessed the blood transcriptome in PPMI PD patients with respect to clinical measures of cognitive impairment, using the MoCA (Montreal Cognitive Assessment) scale, where MoCA > 26 is normal; n=144) and MoCa < 26 is abnormal; n=332) and identified 2508 and 380 up and downregulated RNAs (Fig 8c, TABLE 9A and data not shown). RNAs that were differentially expressed in the caudate in PDD patients, such as TRAPPC6A, ARFRP1, NUCKS1 and STAG3, progressively changed in the blood with worsening MoCA (Fig 7d). TABLE 9A Controls PD- PD- p value p value p Test (n=161) cognitive normal PD- (PD- value impairment cognition cognitive cognitive (PD- (n=144) (n=332) impairme impairme Norma nt vs PD- nt vs l Normal CTRL) cogniti cognition on vs CTRL) Age at collection (years) 59.6 66.3 (8.6) 59.5 5.80E- 5.50E- 0.517 Wilcox (11.3) (9.6) 13 08 on Male / Female 99 / 62 111 / 33 200 / 132 0.0004 0.004 0.844 Fisher test Race 148 / 8 / 1 126 / 2 / 6 / 10 315 / 5 / 3 / 0.012 0.014 0.152 Fisher (White / Black / Hispanic / / 4 9 test Other) Age of onset / diagnosis NA 64.2 (8.7) 57.5 2.60E- NA NA Wilcox (years) (10.0) 12 on Disease duration (years) NA 6.7 (6.3) 6.8 (6.9) 0.993 NA NA Wilcox on quality (% usable bases) 40.7 41.3 (9.0) 41.0 0.730 0.396 0.465 Wilcox (8.5) (9.6) on Mean (standard deviation); p values were determined using listed tests [000228] Interestingly, the top GO terms that differentiated subjects with and without cognitive impairment in the blood were neuronal terms, including glutamatergic signaling (glutamate binding, NMDA glutamate receptor complex, spontaneous neurotransmitter secretion) (Fig 8d, TABLE 9B and additional data not shown). GO terms dysregulated in PDD caudate such as histone H4 acetylation, mitochondrial DNA metabolic process and circadian regulation of gene expression wereinversely changed and also significantly altered in the blood of PPMI subjects with cognitive impairment (Fig 8d,e). As postmortem PDD donors had longer average disease duration (13.4 ± 7.2 years) relative to PPMI PD subjects with cognitive impairment (average disease duration 6.7 ± 6.3 years), these observations suggest that the above stress response pathways are important in development of PDD, and likely undergo dynamic changes early in the course of disease. TABLE 9B – GO terms PD dementia vs no dementia – Blood PATHWAY GO_NEGATIVE_REGULATION_OF_ANION_TRANSMEMBRANE_TRANSPORT GO_NEGATIVE_REGULATION_OF_TOR_SIGNALING GO_GLUTAMATE_BINDING GO_REGULATION_OF_ANION_TRANSMEMBRANE_TRANSPORT GO_GLOMERULUS_VASCULATURE_MORPHOGENESIS GO_RETINOL_BINDING GO_ENDOPLASMIC_RETICULUM_LOCALIZATION GO_POSITIVE_REGULATION_OF_PROTEIN_EXIT_FROM_ENDOPLASMIC_RETICULUM GO_POSITIVE_REGULATION_OF_MICROTUBULE_BINDING GO_REGULATION_OF_GLUCONEOGENESIS GO_MICROTUBULE_NUCLEATION_BY_MICROTUBULE_ORGANIZING_CENTER GO_RNA_POLYMERASE_III_GENERAL_TRANSCRIPTION_INITIATION_FACTOR_ ACTIVITY GO_TRANSCRIPTION_DEPENDENT_TETHERING_OF_RNA_POLYMERASE_II_GENE_ DNA_AT_NUCLEAR_PERIPHERY GO_N_ACYLPHOSPHATIDYLETHANOLAMINE_SPECIFIC_PHOSPHOLIPASE_D_ ACTIVITY GO_HISTONE_ACETYLTRANSFERASE_ACTIVITY_H4_K5_SPECIFIC GO_HISTONE_H4_ACETYLATION GO_REGULATION_OF_INTERLEUKIN_4_PRODUCTION GO_CELLULAR_RESPONSE_TO_LEUCINE_STARVATION GO_N_GLYCAN_PROCESSING GO_SERINE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS GO_COMPLEX_OF_COLLAGEN_TRIMERS GO_MICROTUBULE_NUCLEATION_BY_INTERPHASE_MICROTUBULE_ORGANIZING_ CENTER GO_FATTY_ACID_TRANSMEMBRANE_TRANSPORT GO_CITRATE_METABOLIC_PROCESS GO_REGULATION_OF_PEPTIDYL_LYSINE_ACETYLATION GO_MRNA_CLEAVAGE_INVOLVED_IN_MRNA_PROCESSING GO_PEPTIDYL_LYSINE_ACETYLATION GO_INTERLEUKIN_4_PRODUCTION GO_MESENCHYMAL_TO_EPITHELIAL_TRANSITION_INVOLVED_IN_METANEPHROS_MORPHOG ENESIS GO_HISTONE_H4_K5_ACETYLATION GO_SPONTANEOUS_NEUROTRANSMITTER_SECRETION GO_PHOSPHATIDYLINOSITOL_BIOSYNTHETIC_PROCESS GO_NMDA_SELECTIVE_GLUTAMATE_RECEPTOR_COMPLEXGO_CARDIOLIPIN_METABOLIC_PROCESS GO_MOTOR_BEHAVIOR GO_PROTEIN_SUMOYLATION GO_DETECTION_OF_STIMULUS GO_NURD_COMPLEX GO_CARDIAC_MYOFIBRIL_ASSEMBLY GO_MUSCLE_CELL_CELLULAR_HOMEOSTASIS GO_POSITIVE_REGULATION_OF_TRANSCRIPTION_BY_RNA_POLYMERASE_III GO_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS GO_CELLULAR_RESPONSE_TO_GLUCOSE_STARVATION GO_REGULATION_OF_POSTTRANSCRIPTIONAL_GENE_SILENCING GO_TYPE_5_METABOTROPIC_GLUTAMATE_RECEPTOR_BINDING GO_METANEPHRIC_MESENCHYMAL_CELL_DIFFERENTIATION GO_GENE_SILENCING_BY_RNA GO_EMBRYONIC_CAMERA_TYPE_EYE_MORPHOGENESIS GO_LIGASE_ACTIVITY_FORMING_CARBON_NITROGEN_BONDS GO_HYDROLASE_ACTIVITY_ACTING_ON_ESTER_BONDS GO_TRANSCRIPTION_INITIATION_FROM_RNA_POLYMERASE_III_PROMOTER GO_PROTEIN_ACETYLATION GO_TRICARBOXYLIC_ACID_METABOLIC_PROCESS GO_SWI_SNF_COMPLEX GO_MITOGEN_ACTIVATED_PROTEIN_KINASE_P38_BINDING GO_REGULATION_OF_GENE_SILENCING GO_MANNOSIDASE_ACTIVITY GO_PINOSOME GO_ATPASE_COMPLEX GO_CELLULAR_RESPONSE_TO_COLD GO_GENE_SILENCING GO_PHOSPHOLIPID_DEPHOSPHORYLATION GO_POSITIVE_REGULATION_OF_PEPTIDYL_LYSINE_ACETYLATION GO_VASODILATION GO_PHOSPHATIDYLINOSITOL_4_5_BISPHOSPHATE_PHOSPHATASE_ACTIVITY GO_MLL1_2_COMPLEX GO_EQUATORIAL_MICROTUBULE_ORGANIZING_CENTER GO_B_CELL_LINEAGE_COMMITMENT GO_PHOSPHATIDYLINOSITOL_PHOSPHATE_5_PHOSPHATASE_ACTIVITY GO_REGULATION_OF_MICROTUBULE_BINDING GO_H3_HISTONE_ACETYLTRANSFERASE_COMPLEX GO_EMBRYONIC_DIGESTIVE_TRACT_MORPHOGENESIS GO_REGULATION_OF_PROTEIN_ACETYLATION GO_PEPTIDYL_LYSINE_TRIMETHYLATION GO_MUSCLE_FIBER_DEVELOPMENT GO_EPITHELIAL_TUBE_BRANCHING_INVOLVED_IN_LUNG_MORPHOGENESIS GO_PROTEIN_DNA_COMPLEX_DISASSEMBLYGO_IONOTROPIC_GLUTAMATE_RECEPTOR_ACTIVITY GO_GPI_ANCHOR_TRANSAMIDASE_COMPLEX GO_GPI_ANCHOR_TRANSAMIDASE_ACTIVITY GO_DIOXYGENASE_ACTIVITY GO_NCRNA_EXPORT_FROM_NUCLEUS GO_IMMUNOLOGICAL_SYNAPSE_FORMATION GO_TRANSMITTER_GATED_CHANNEL_ACTIVITY GO_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC GO_PEPTIDYL_LYSINE_MODIFICATION GO_RNA_POLYMERASE_III_TRANSCRIPTION_FACTOR_COMPLEX GO_DNA_METHYLATION_OR_DEMETHYLATION GO_ACTIVATION_INDUCED_CELL_DEATH_OF_T_CELLS GO_AXONEMAL_DYNEIN_COMPLEX GO_MITOCHONDRIAL_DNA_METABOLIC_PROCESS GO_MICROTUBULE_MINUS_END_BINDING GO_OUTER_DYNEIN_ARM GO_REGULATION_OF_PROTEIN_EXIT_FROM_ENDOPLASMIC_RETICULUM GO_POSITIVE_REGULATION_OF_CHROMATIN_SILENCING GO_REGULATION_OF_METHYLATION_DEPENDENT_CHROMATIN_SILENCING GO_INO80_TYPE_COMPLEX GO_PHOSPHATIDYLINOSITOL_DEPHOSPHORYLATION GO_CIRCADIAN_REGULATION_OF_GENE_EXPRESSION GO_PHOSPHATIDYLINOSITOL_BISPHOSPHATE_PHOSPHATASE_ACTIVITY GO_GLUTAMATE_RECEPTOR_ACTIVITY GO_LUNG_MORPHOGENESIS GO_FOREBRAIN_REGIONALIZATION GO_PATTERN_SPECIFICATION_INVOLVED_IN_KIDNEY_DEVELOPMENT GO_CEREBELLAR_PURKINJE_CELL_GRANULE_CELL_PRECURSOR_CELL_SIGNALING_INVOLVE D_IN_REGULATION_OF_GRANULE_CELL_PRECURSOR_CELL_PROLIFERATION GO_GLUTAMATE_GATED_CALCIUM_ION_CHANNEL_ACTIVITY GO_DEVELOPMENTAL_INDUCTION GO_RNA_SPLICING_VIA_ENDONUCLEOLYTIC_CLEAVAGE_AND_LIGATION GO_OUTER_EAR_MORPHOGENESIS GO_MONOSACCHARIDE_BIOSYNTHETIC_PROCESS GO_ENDOPLASMIC_RETICULUM_UNFOLDED_PROTEIN_RESPONSE GO_POSTSYNAPTIC_NEUROTRANSMITTER_RECEPTOR_ACTIVITY GO_REGULATION_OF_INSULIN_LIKE_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY GO_METHYLATION_DEPENDENT_CHROMATIN_SILENCING GO_PROTEIN_ACYLATION GO_EXTRINSIC_COMPONENT_OF_MITOCHONDRIAL_INNER_MEMBRANE GO_CILIARY_BASE GO_MESODERMAL_CELL_FATE_COMMITMENT GO_HISTONE_H4_K16_ACETYLATION GO_SYNAPTIC_TRANSMISSION_GLUTAMATERGICGO_PHOSPHORIC_ESTER_HYDROLASE_ACTIVITY GO_PROTEIN_EXIT_FROM_ENDOPLASMIC_RETICULUM GO_CHANGES_TO_DNA_METHYLATION_INVOLVED_IN_EMBRYO_DEVELOPMENT GO_NEUROTRANSMITTER_RECEPTOR_ACTIVITY_INVOLVED_IN_REGULATION_OF_POSTSYNA PTIC_MEMBRANE_POTENTIAL GO_N_ACETYLTRANSFERASE_ACTIVITY GO_FRUCTOSE_METABOLIC_PROCESS GO_PHOSPHATIDYLINOSITOL_3_KINASE_COMPLEX GO_NUCLEAR_TRANSCRIPTIONAL_REPRESSOR_COMPLEX GO_IMMUNOLOGICAL_SYNAPSE GO_REGULATION_OF_TRANSCRIPTION_INVOLVED_IN_CELL_FATE_COMMITMENT GO_INTEGRATOR_COMPLEX GO_LIPOSACCHARIDE_METABOLIC_PROCESS GO_PHOSPHATIDYLINOSITOL_PHOSPHATE_PHOSPHATASE_ACTIVITY GO_RNA_POLYMERASE_II_C_TERMINAL_DOMAIN_BINDING GO_2_OXOGLUTARATE_DEPENDENT_DIOXYGENASE_ACTIVITY [000229] Although PPMI PD subjects who were drug-naive for dementia medications had significantly better cognitive profiles (Fig 8f), many RNAs and pathways nonetheless showed similar expression patterns with decreasing MoCA scores (Fig 8g,h). These studies indicate that RNAs associated with dementia in the brain show corresponding changes in the blood with worsening cognition. [000230] We next assessed the molecular changes in caudate and putamen in PD subjects with a clinical history of levodopa-induced dyskinesia (TABLE 10A, see Methods), although only a small numbers of comparable donors with (n=5) or without (n=11) dyskinesia were available for analysis. There was no significant difference in the average LEDD between donors with (average LEDD 716.3 + / - 577.5 mg) and without dyskinesia (average LEDD 954.7 + / - 780.1 mg). Differential gene expression analysis identified 18 RNAs which were altered in the putamen (TABLE 10B), while few RNAs (only 1 RNA) were differentially expressed in the caudate (TABLE 10C) (Fig 9a, data not shown). We assessed transcriptome patterns in the blood of PPMI subjects with (n=213) and without (n=201) history of dyskinesia, but did not observe any significant difference between these groups (data not shown). In contrast to patients with PDD, where changes were preferentially observed in the caudate, patients with dyskinesia had differentially changed GO terms specifically in the putamen (Fig 9b, TABLE 10D). The caudate was not significantly affected in dyskinesia, while the putamen is selectively affected in dyskinesia. These observations were consistent with previous functional imaging studies in PD patients and animal models of PD, showing vascular pathology in the putamen in levodopa-induced dyskinesia49–52. Here, we identified differences in regulation of endothelial cell pathology and cell death GO terms (endothelial cell apoptosis, anoikis, vascular permeability, fluid laminar shear stress, death receptor signaling; Fig 9c,d). Taken together, our results suggest that PDpatients with cognitive and motor complications have distinct molecular changes in the caudate and putamen respectively, some of which are reflected in the antemortem blood transcriptome. TABLE 10A Control Dys No Dys Yes p p value p value Test (n=40) (n=11) (n=5) value (No vs (Yes vs (Yes CTRL) CTRL) vs No) Age of death 72.4 (11.8) 73.2 76.4 0.362 0.606 0.303 Wilcoxon (years) (6.1) (6.7) Male / Female 28 / 12 10 / 1 5 1 0.25 0.303 Fisher (Male) Race 34 / 2 / 2 / 2 4 10 0.125 1 1 Fisher (White / Black / H (White) / (White) ispanic / Other) 2 (Black) Age of NA 62.1 59.0 0.359 NA NA Wilcoxon onset / diagnosis (8.0) (6.7) (years) Disease NA 12.9 13.4 1 NA NA Wilcoxon duration (years) (6.9) (7.2) PMI (hours) 16.9 (7.6) 17.7 24.6 0.441 0.837 0.187 Wilcoxon (9.5) (13.4) RIN (PUT) 6.6 (1.9) 5.5 (2.6) 5.1 (2.5) 0.865 0.63 0.357 Wilcoxon RIN (CAU) 6.6 (1.8) 5.5 (2.2) 5.3 (2.6) 0.91 0.092 0.248 Wilcoxon Mean (standard deviation); p values were calculated using listed tests TABLE 10B – Putamen RNAs Dyskinesia ID logFC AveExpr t P.Value adj.P.Val B NGF -3.5563286 -1.5449134 -5.7971906 6.60E-08 0.00133031 5.34949094 EXOC3L1 -1.7588907 0.79789358 -4.955336 2.65E-06 0.01779438 4.08943701 CCDC172 -2.6676869 -1.8179418 -5.2642353 7.08E-07 0.00713621 3.67997002 ITGB3 -2.0258529 0.18335372 -4.6755028 8.42E-06 0.0423871 2.96566885 STX17-AS1 1.0778987 0.09001957 4.52437705 1.55E-05 0.06225501 2.54278191 VWA2 -1.7276366 1.03895519 -4.3758181 2.77E-05 0.07082941 2.17371376 DACT1 1.19463199 2.14693836 4.26754712 4.22E-05 0.07915671 1.94990916 CPTP -0.8780703 4.24644636 -4.2378645 4.73E-05 0.07915671 1.79604048 LINC01574 -2.4850502 -0.7598421 -4.4158878 2.37E-05 0.07082941 1.68303067 C1QTNF3- 2.64193335 1.2781826 4.18663127 5.74E-05 0.07915671 1.63398876 AMACR MIER2 -0.7296487 4.24555016 -4.1714973 6.08E-05 0.07915671 1.56237206 C9orf129 -2.7490534 -0.5921343 -4.2409124 4.67E-05 0.07915671 1.26535179 SLCO4A1- -3.7351468 -1.2246675 -4.3496622 3.07E-05 0.07082941 1.2538872 AS1 EFCC1 -2.0161379 0.03777933 -4.162803 6.29E-05 0.07915671 1.22976739 TMEM115 -0.5390778 4.77717194 -4.0785792 8.63E-05 0.09653497 1.21704441 C1orf116 -2.5210879 -2.1256911 -4.3420251 3.16E-05 0.07082941 0.93541 DNAH8 2.36750563 -1.5732021 4.12643284 7.21E-05 0.08544571 0.87982896CAGE1 -2.8436571 -2.4547459 -4.2008486 5.44E-05 0.07915671 0.41547423 TABLE 10C – Caudate RNAs Dyskinesia ID logFC AveExpr t P.Value adj.P.Val B FREM1 2.26636522 0.49112821 4.95917792 2.61E-06 0.05252876 2.48254195 TABLE 10D – GO Terms Putamen Dyskinesia PATHWAY GO_ENTRAINMENT_OF_CIRCADIAN_CLOCK GO_CHEMOKINE_C_X_C_MOTIF_LIGAND_2_PRODUCTION GO_ANOIKIS GO_NEGATIVE_REGULATION_OF_ENDOTHELIAL_CELL_APOPTOTIC_PROCESS GO_ENTRAINMENT_OF_CIRCADIAN_CLOCK_BY_PHOTOPERIOD GO_PHOTOPERIODISM GO_POSITIVE_REGULATION_OF_URINE_VOLUME GO_CHOLESTEROL_STORAGE GO_ENDOTHELIAL_CELL_APOPTOTIC_PROCESS GO_DEATH_RECEPTOR_BINDING GO_BHLH_TRANSCRIPTION_FACTOR_BINDING GO_MIDDLE_EAR_MORPHOGENESIS GO_REGULATION_OF_NOTCH_SIGNALING_PATHWAY GO_KERATINOCYTE_DEVELOPMENT GO_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_APOPTOTIC_PROCESS GO_POSITIVE_REGULATION_OF_DIGESTIVE_SYSTEM_PROCESS GO_REGULATION_OF_VASCULAR_PERMEABILITY GO_RESPONSE_TO_LAMINAR_FLUID_SHEAR_STRESS GO_METANEPHRIC_GLOMERULUS_DEVELOPMENT [000231] Clinical-Molecular Analysis: Age of Onset [000232] Patients with late onset PD are clinically distinct from patients with early onset of disease, with late onset PD patients experiencing faster motor and non-motor progression of disease compared to early onset PD patients53–55. While the classic definition of early onset is arbitrary, with ages ranging from <40 to <50, previous studies have shown that for every decade for onset studied, older age of onset was associated with worse motor and non-motor disease.This led us to hypothesize that there may be distinct molecular features in the striatum that distinguish the age of PD onset. [000233] PCA revealed that patients with later age of onset (referred to as LOPD, age of onset > 55) separated better from controls, more than patients (n=6) with earlier onset of PD (referred here as EOPD, age of onset < 55) (Fig 10a, TABLE 11). After factoring in age at death, differential gene expression analysis in the caudate of LOPD patients identified 5266 and 5723 RNAs that were significantly up or downregulated, respectively (Fig 10b, data not shown). In the putamen of LOPD patients, 5599 and 6551 RNAs were up or downregulated, respectively (Fig 10b, data not shown).Using more stringent criteria, 1357 differentially expressed genes were identified in caudate (LOPD vs control) and 2089 genes in putamen (LOPD vs control) (data not shown). LOPD brains showed differentially expressed RNAs compared to controls even when small sample numbers were used (n=6), again suggesting that changes in LOPD striatum are robust (Fig 11a,b). In contrast, few differentially expressed RNAs could be identified between EOPD patients and controls (Fig 10b, Fig 11b, data not shown). TABLE 11 Control EOPD (n=6) LOPD p value p value p value Test (n=40) (n=25) (LOPD (EOPD (LOPD vs vs vs EOPD) CTRL) CTRL) Age of death 72.4 71.3 (5.2) 77.1 (6.9) 0.014 0.857 0.003 Wilcoxon (years) (11.8) Male / Female 28 / 12 5 / 1 19 / 6 1 0.66 0.777 Fisher Race 34 / 2 / 2 / 5 (White) / 1 23 0.488 0.652 0.904 Fisher (White / Black / Hisp 2 (Black) (White) / 1 anic / Other) (Black) / 1 (Hispanic ) Age of NA 50.5 (3.7) 66.0 (7.2) 8.90E- NA NA Wilcoxon onset / diagnosis 08 (years) Disease duration NA 20.5 (5.1) 11.2 (5.9) 0.005 NA NA Wilcoxon (years) PMI (hours) 16.9 18.8 (5.8) 18.8 (5.8) 0.94 0.613 0.422 Wilcoxon (7.6) RIN (CAU) 6.6 6.4 (2.1) 5.6 (1.9) 0.305 0.974 0.026 Wilcoxon (1.8) RIN (PUT) 6.6 6.6 (2.0) 5.4 (2.0) 0.154 0.883 0.037 Wilcoxon (1.9) Mean (standard deviation); p values were calculated using listed tests [000234] Calcium ion transport was the top changed GO term in LOPD, consistent with significant synaptic dysregulation seen in PD. Gene set enrichment scores showed significant downregulation of this pathway in LOPD, while EOPD patients showed no significant differences relative to controls (Fig 10c, data not shown). A more targeted approach, looking at dopaminergic pathway differences, showed the same differences in molecular impact in LOPD but not EOPD (Fig 10c). Notably, these differences were seen despite the shorter disease duration in LOPD (11.24 ± 5.9 years) compared to EOPD (20.50 ± 5.1 years). [000235] Functional imaging studies in PPMI subjects have demonstrated that dopamine dysfunction is comparable in the putamen in late and early onset PD54. Postmortem studies have suggested that there is substantial loss of DA input into the putamen within 5 years of disease onset, although this has not been investigated in the context of age of onset of disease56. Given the lack of molecular changes in EOPD, we tested the hypothesis that this was secondary to preserved dopamine input inthese patients. We assessed TH levels on protein extracts from caudate and putamen of donors with EOPD and LOPD to estimate loss of dopaminergic innervation in these groups. Both EOPD and LOPD showed comparable loss of TH (Fig 11c,d). These observations show that despite the substantial and comparable loss of nigral dopamine input and shorter disease duration compared to EOPD, LOPD patients show significant RNA changes compared to controls. Taken together, these data suggest physiologic differences in how the striatum responds to dopamine loss in EOPD and LOPD. [000236] We next analyzed the blood transcriptome from controls (n=195), LOPD (n=330) and EOPD (n=149) individuals from the PPMI cohort (TABLE 12). Similar to our observations in the caudate and putamen, significant blood RNA changes were evident in LOPD but not EOPD (Fig 10d, data not shown). These observations suggest that LOPD and EOPD are fundamentally different in their molecular characteristics in the caudate and putamen, and these differences are mirrored in the blood. TABLE 12 Controls EOPD LOPD p p p Test (n=195) (n=149) (n=330) value value value (EOPD (EOPD (LOP vs vs D vs LOPD) CTRL) CTRL Age at collection 60.8 50.1 (6.0) 66.8 4.5E-66 8.7E- 2.0E- Wilcoxon (years) (11.3) (5.9) 25 10 Male / Female 125 / 70 83 / 66 228 / 102 0.005 1.1E- 5.1E- Fisher 08 13 test Race 180 / 10 / 1 / 308 / 5 / 89 136 / 2 / 1 / 0.130 0.029 0.039 Fisher (White / Black / Hispanic / 4 10 test Other) Age of onset / diagnosis NA 47.5 65.0 8.5E-69 NA NA Wilcoxon (years) (6.05) (5.9) Disease duration NA 7.6 (8.1) 6.4 (6.0) 0.630 NA NA Wilcoxon (years) quality (% usable 41.0 (8.4) 42.0 40.7 0.119 0.151 0.965 Wilcoxon bases) (10.0) (9.1) Mean (standard deviation); p values were determined using listed tests [000237] Clinical-Molecular Analysis: Disease Duration [000238] Previous studies have shown an association between disease duration and loss of dopamine input into the striatum56. This association was non-linear, with the greatest loss of dopamine input into the putamen occurring in the first four years after diagnosis. We used spline interpolation in the brain to investigate relationships between gene expression and disease duration in the striatum. GO terms significantly associated with disease duration in the caudate included oligodendrocyte development, pinocytosis and gonadotropin response pathway, consistent with extra-hypothalamic gonadotropin expressing population discovered in the striatum57(Fig 12a,c and data not shown). In the putamen, GO terms associated with increased disease duration include nuclear hormone receptor binding,integrin signaling and cellular senescence (p38 MAP kinase, cell aging) (Fig 12b,d and data not shown). In PD putamen, many pathways showed downregulation with long (> 20 years) disease duration, which may reflect the dynamic changes that occur in the final stages of disease. In sum, these observations highlight the temporal dynamics of molecular pathways and the continuous accumulation of pathology in PD caudate and putamen over the course of the disease, from onset to death. DISCUSSION [000239] Loss of dopamine input into the striatum is one of the key mechanisms underlying clinical manifestations in PD. At the time of diagnosis of PD, most patients have lost roughly 60% of the nigral dopamine neurons3. Although the initial loss of dopamine input is balanced by compensatory mechanisms in the striatum, eventually, striatal dysfunction leads to onset of symptoms58. Therefore, understanding the molecular changes in the striatum in PD has a vast potential for disease modulation. Moreover, the biological and molecular basis for clinical heterogeneity seen in PD is not understood. Identifying molecular features in blood that correlate with pathological changes in the brain and clinical trajectories offer predictive value for patients early in the course of disease. Here we present an in-depth molecular analysis of the PD striatum and correlate molecular changes in the striatum with clinical variables. We discovered that the caudate and putamen show both overlapping and distinct transcriptome changes with the caudate particularly affected in PD patients with cognitive impairment while putamen is more affected in motor complications such as dyskinesia. We show that LOPD is molecularly distinct from EOPD, even at the end of their disease course. Finally, we identify that molecular signatures of PD and its clinical heterogeneity can be identified in the peripheral blood antemortem which could ultimately be clinically useful for prognosis and treatment. [000240] We observed that several GO terms previously linked to the death of substantia nigra dopaminergic neurons including immune response, synaptic signaling, and mitochondrial dynamics were also altered in the striatum, thus indicating a global dysregulation of these pathways in PD1,59. In PDD caudate, we observed an upregulation of pathways linked to memory formation in mice, such as histone acetylation and protein kinase C signaling60–62and mitochondrial DNA metabolism, consistent with a previous study in the PDD prefrontal cortex63. As dopamine is a potent modulator of circadian rhythm through D2 receptor64and PDD caudate shows changes in circadian regulation, it is of future interest to understand if there is a bidirectional relationship between cognitive decline and PD-related circadian sleep disorders, as seen in Alzheimer’s disease65. Functional imaging studies have shown abnormal putaminal neurovascular responses in patients with levodopa-induced dyskinesia52, linked to increased endothelial proliferation, neo-angiogenesis and blood-brain barrier permeability49–51. Our discovery of dysregulated vascular endothelial pathways provides molecular confirmation of these mechanisms in PD patients with levodopa-induced dyskinesia. [000241] The more robust molecular changes in LOPD than EOPD, despite their longer disease duration and comparable loss of dopaminergic innervation, may explain the faster disease progressionin late onset PD patients53and indicate different pathophysiologies and response to dopamine loss in the two groups. As RNA changes associated with age of death in the two groups were factored in our comparative analysis, there is likely an additive...

Claims

WHAT IS CLAIMED IS:

1. A method for assessing or evaluating Parkinson’s disease (PD) in a patient or individual comprising: (a) isolating a sample from said patient; (b) evaluating the sample for expression or quantitatively increased or decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 4; (ii) markers as provided in Table 13 or 14; (iii) markers as provided in Table 23, 24, 25 or 26; (iv) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4; (v) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL, CAMK4, FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; and (vi) markers selected from FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (c) wherein the expression or quantitatively increased or decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) in a patient or individual.

2. The method of claim 1 for assessing or evaluating Parkinson’s disease (PD) in a patient or individual comprising: (a) isolating a sample from said patient; (b) evaluating the sample for expression or quantitatively increased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 14; (ii) markers as provided in Table 23 or 25; and (iii) markers selected from FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (c) wherein the expression or quantitatively increased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) in a patient or individual.

3. The method of claim 1 for assessing or evaluating Parkinson’s disease (PD) in a patient or individual comprising: (a) isolating a sample from said patient; (b) evaluating the sample for expression or quantitatively decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 13;(ii) markers as provided in Table 24 or 26; (iii) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4; and (iv) markers selected from GPR52, SNCA, DNAJC6 and DLG2; (c) wherein the expression or quantitatively decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) in a patient or individual.

4. The method of claim 1, wherein a blood sample is isolated and evaluated for expression or quantitatively increased or decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (ii) markers as provided in Table 13 or 14; (iii) markers as provided in Table 23, 24, 25 or 26; (iv) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4; (v) markers selected from FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; and (vi) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL, CAMK4, FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (c) wherein the expression or quantitatively increased or decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) in a patient or individual.

5. The method of claim 2, wherein a blood sample is isolated and evaluated for expression or quantitatively increased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 14; (ii) markers as provided in Table 23 or 25; and (iii) markers selected from FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (c) wherein the expression or quantitatively increased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) in a patient or individual.

6. The method of claim 3, wherein a blood sample is isolated and evaluated for expression or quantitatively decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 13; (ii) markers as provided in Table 24 or 26;(iii) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4; and (iv) markers selected from GPR52, SNCA, DNAJC6 and DLG2; (c) wherein the expression or quantitatively decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) in a patient or individual.

7. A method for assessing or evaluating Parkinson’s disease with dementia (PDD) in a patient or individual comprising: (a) isolating a sample from said patient; (b) evaluating the sample for expression or quantitatively increased or decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 15, 16, 17, 18, 19, 27 or 28; (ii) markers as provided in Table 27 or 28; (iv) markers selected from TRAPPC6A, NUCKS1, STAG3 and ARFRP1; (v) markers selected from MARS1, NFAT5, LONRF3, PPP1R15B and TARS1; (vi) markers selected from NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115; (vii) markers selected from STX17AS1, DACT1, DNAH8 and C1QTNF3- AMACR; (vii) markers selected from TRAPPC6A, NUCKS1, STAG3, ARFRP1, NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2, TMEM115, MARS1, NFAT5, LONRF3, PPP1R15B, TARS1, STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR; (viii) markers selected from TRAPPC6A, NUCKS1, STAG3, ARFRP1, NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115; (vii) markers selected from MARS1, NFAT5, LONRF3, PPP1R15B, TARS1 STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR; and (c) wherein the expression or quantitatively increased or decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease with dementia (PDD) in a patient or individual.

8. The method of claim 7 for assessing or evaluating Parkinson’s disease with dementia (PDD) in a patient or individual comprising: (a) isolating a sample from said patient; (b) evaluating the sample for expression or quantitatively increased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from:(i) markers as provided in Table 16 or 18; (ii) markers selected from MARS1, NFAT5, LONRF3, PPP1R15B and TARS1; (iii) markers selected from STX17AS1, DACT1, DNAH8 and C1QTNF3- AMACR; (iv) markers selected from MARS1, NFAT5, LONRF3, PPP1R15B, TARS1 STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR; and (c) wherein the expression or quantitatively increased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease with dementia (PDD) in a patient or individual.

9. The method of claim 7 for assessing or evaluating Parkinson’s disease with dementia (PDD) in a patient or individual comprising: (a) isolating a sample from said patient; (b) evaluating the sample for expression or quantitatively decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 15 or 17; (ii) markers selected from TRAPPC6A, NUCKS1, STAG3 and ARFRP1; (ii) markers selected from NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115; and (iv) markers selected from TRAPPC6A, NUCKS1, STAG3, ARFRP1, NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115; (c) wherein the expression or quantitatively decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease with dementia (PDD) in a patient or individual.

10. The method of claim 7, wherein a blood sample is isolated and evaluated for expression or quantitatively increased or decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 27 or 28; (c) wherein the expression or quantitatively increased or decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease with dementia (PDD) in a patient or individual.

11. A method for assessing or evaluating Parkinson’s disease (PD) with dyskinesia in a patient or individual comprising: (a) isolating a sample from said patient;(b) evaluating the sample for expression or quantitatively increased or decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 20; (ii) markers as provided in Table 29 and / or 30; and (iv) markers selected from FTCDNL1, MAF1, THEM4, TSTA3, XKRX, KANSL1-AS1, NUDT15, LINC00269, TMEM80, TMPO-AS1, ALAS2, TUBB4B, AHSP, EIF3C, WDR45, KIFC3 and CDC34; (c) wherein the expression or quantitatively increased or decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) with dyskinesia in a patient or individual.

12. The method of claim 11, wherein a blood sample is isolated and evaluated for expression or quantitatively increased or decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 29 and / or 30; and (ii) markers selected from FTCDNL1, MAF1, THEM4, TSTA3, XKRX, KANSL1-AS1, NUDT15, LINC00269, TMEM80, TMPO-AS1, ALAS2, TUBB4B, AHSP, EIF3C, WDR45, KIFC3 and CDC34; (c) wherein the expression or quantitatively increased or decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) with dyskinesia in a patient or individual.

13. A method for assessing or evaluating Parkinson’s disease (PD) with disease duration in a patient or individual comprising: (a) isolating a sample from said patient; (b) evaluating the sample for expression or quantitatively increased or decreased amounts of one or more sets of gene markers, RNA markers, or associated protein markers selected from: (i) markers as provided in Table 21 and / or 22; (c) wherein the expression or quantitatively increased or decreased amounts of the marker gene expression, RNA or encoded protein is associated with and indicative of Parkinson’s disease (PD) with dyskinesia in a patient or individual.

14. The method of any of claims 1-13, wherein a subset of at least 20 of the markers are evaluated.

15. The method of any of claims 1-13, wherein a subset of at least 10 of the markers are evaluated.

16. The method of any of claims 1-13, wherein a subset of at least 4 of the markers are evaluated.

17. The method of any of claims 1-13, wherein all of the markers listed in at least one set of markers are evaluated.

18. The method of any of claims 1-13, wherein RNA expression is assessed by RT PCR.

19. The method of any of claims 1-13, wherein protein expression is assessed using specific antibodies.

20. The method of any of claims 1-13, further comprising treating the patient thereby diagnosed with Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), PD with dyskinesia, or PD with disease duration by administering a therapeutically effective amount of one or more agent or therapy for treating PD, dementia, or dyskinesia.

21. A set of RNA or protein markers for assessing or evaluating Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), Parkinson’s disease dyskinesia or Parkinson’s with disease duration in a patient comprising the markers selected from: (i) markers as provided in Table 4; (ii) markers as provided in Table 13 or 14; (iii) markers as provided in Table 23, 24, 25 or 26; (iv) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4; (v) markers selected from FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (vi) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL, CAMK4, FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (vii) markers selected from GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4; and (viii) markers selected from FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (ix) markers as provided in Table 15, 16, 17, 18, 19, 27 or 28; (x) markers as provided in Table 27 or 28; (xi) markers selected from TRAPPC6A, NUCKS1, STAG3 and ARFRP1; (xii) markers selected from MARS1, NFAT5, LONRF3, PPP1R15B and TARS1; (xiii) markers selected from NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115; (xiv) markers selected from STX17AS1, DACT1, DNAH8 and C1QTNF3- AMACR;(xv) markers selected from TRAPPC6A, NUCKS1, STAG3, ARFRP1, NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2, TMEM115, MARS1, NFAT5, LONRF3, PPP1R15B, TARS1, STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR; (xvi) markers selected from TRAPPC6A, NUCKS1, STAG3, ARFRP1, NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115; (xvii) markers selected from MARS1, NFAT5, LONRF3, PPP1R15B, TARS1 STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR; and (xviii) markers as provided in Table 20; (xix) markers as provided in Table 29 and / or 30; and (xx) markers selected from FTCDNL1, MAF1, THEM4, TSTA3, XKRX, KANSL1-AS1, NUDT15, LINC00269, TMEM80, TMPO-AS1, ALAS2, TUBB4B, AHSP, EIF3C, WDR45, KIFC3 and CDC34; and (xxi) markers as provided in Table 21 an / or 22.

22. A system or kit for assessing or evaluating Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), Parkinson’s disease dyskinesia or Parkinson’s with disease duration in a patient comprising a set of markers of claim 20 or a set of probes and / or antibodies for evaluating a set of markers of claim 20.

23. The system or kit of claim 22, comprising a set of probes and / or antibodies for evaluating a set of markers selected from: (i) markers GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4; (ii) markers FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (iii) markers GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL, CAMK4, FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (iv) markers GPR52, SNCA, DNAJC6, DLG2, TIAM1, TOMM70, PREPL and CAMK4; and (v) markers FCAR, PROK2, IL1R2, HSPA6 and CHRNA10; (vi) markers TRAPPC6A, NUCKS1, STAG3 and ARFRP1; (vii) markers MARS1, NFAT5, LONRF3, PPP1R15B and TARS1; (viii) markers NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115; (ix) markers STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR;(x) markers TRAPPC6A, NUCKS1, STAG3, ARFRP1, NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2, TMEM115, MARS1, NFAT5, LONRF3, PPP1R15B, TARS1, STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR; (xi) markers TRAPPC6A, NUCKS1, STAG3, ARFRP1, NGF, CCDC172, EXOC3L1, ITGB3, VWA2, C1orf116, CAGE1, C9orf129, CPTP, EFCC1, MIER2 and TMEM115; (xii) markers MARS1, NFAT5, LONRF3, PPP1R15B, TARS1 STX17AS1, DACT1, DNAH8 and C1QTNF3-AMACR; and (xiii) markers FTCDNL1, MAF1, THEM4, TSTA3, XKRX, KANSL1-AS1, NUDT15, LINC00269, TMEM80, TMPO-AS1, ALAS2, TUBB4B, AHSP, EIF3C, WDR45, KIFC3 and CDC34.