Microglial gene silencing using double-stranded siRNA

Abstract

Microglia is an integral part of the immune system in the central nervous system and is also a potential cause of disease. Gene silencing uses short interfering RNA (siRNA) to selectively target genes that are the cause of such diseases. By using branched siRNA, the distribution of siRNA throughout the CNS, including resident microglial cells, can be enhanced compared to non-branched siRNA. Methods and compositions for the use of branched siRNA in therapy are included herein.

Description

[Technical field]

[0001] The present application relates to a method for delivering branched siRNA molecules, and to branched siRNA molecules, etc. [Background technology]

[0002] In many species, the introduction of double-stranded RNA (dsRNA) induces strong and specific gene silencing. This phenomenon occurs in both plants and animals and plays a role in viral defense and transposon silencing mechanisms. Short interfering RNA (siRNA), which is generally much shorter than the target gene, has been shown to be effective in gene silencing.

[0003] Microglia are a type of glial cell found in the central nervous system (CNS). Microglia are an essential component of the CNS immune system, but microglia with dysregulated genes can also cause disease. For example, disease states can be caused as a result of overactive microglial genes or genes with reduced expression and / or activity in microglia. Summary of the Invention [Problem to be solved by the invention]

[0004] Thus, silencing of effector genes or pathway regulator genes may be necessary to restore normal gene network function and ameliorate disease states.Therefore, new and improved therapeutic approaches are needed that can infiltrate microglial cells and silence microglial genes to restore microglial genetic and biochemical pathway activity from disease states to normal healthy states. [Means for solving the problem]

[0005] In one aspect, the invention features a method of delivering a branched small interfering RNA (siRNA) molecule to microglial cells of a subject in need of microglial gene silencing. The method can include administering the branched siRNA molecule to the subject (e.g., to the central nervous system of the subject).

[0006] In some embodiments, the subject has been diagnosed with a disease associated with dysregulated microglial gene or dysregulated microglial gene pathway expression, hi some embodiments, the subject has been diagnosed with a disease associated with dysregulated microglial gene expression and / or activity (e.g., altered expression and / or activity of wild-type or mutant microglial genes).

[0007] In some embodiments, the dysregulated microglial gene exhibits increased expression and / or activity in the microglial cells of the subject compared to the expression and / or activity of the microglial gene in the microglial cells of a reference subject. In some embodiments, the dysregulated microglial gene exhibits reduced expression and / or activity in the microglial cells of the subject compared to the expression and / or activity of the microglial gene in the microglial cells of a reference subject.

[0008] In some embodiments, the microglial gene is a positive regulator of a gene whose increased expression and / or activity compared to the levels of expression and / or activity observed in a reference subject is associated with a disease state.

[0009] In some embodiments, the microglial gene is a negative regulator of a gene whose reduced expression and / or activity compared to the levels of expression and / or activity observed in a reference subject is associated with a disease state.

[0010] In some embodiments, the microglial gene is a splice isoform of a gene for which overexpressed splice isoforms relative to expression of a reference splice isoform are associated with a disease state.

[0011] In some embodiments, the disease is a neuroinflammatory disease or a neurodegenerative disease. In some embodiments, the disease is Alzheimer's disease. In some embodiments, the disease is amyotrophic lateral sclerosis. In some embodiments, the disease is Parkinson's disease. In some embodiments, the disease is frontotemporal dementia. In some embodiments, the disease is Huntington's disease. In some embodiments, the disease is multiple sclerosis. In some embodiments, the disease is progressive supranuclear palsy.

[0012] In some embodiments, the dysregulated microglial genes are ABCA7, ABI3, ADAM10, APOC1, APOE, AXL, BIN1, C1QA, C3, C9ORF72, CASS4, CCL5, CD2AP, CD33, CD68, CLPTM1, CLU, CR1, CSF1, CST7, CTSB, CTSD, CTSL, CXCL10, CXCL13, DSG2, ECHDC3, EPHA1, FABP5, FERMT2, FTH1, GNAS, GRN, HBEGF, HLA-DRB1, HLA-DRB5, IFIT1, I Selected from the group consisting of FIT3, IFITM3, IFNAR1, IFNAR2, IGF1, IL10RA, IL1A, IL1B, IL1RAP, INPP5D, ITGAM, ITGAX, LILRB4, LPL, MEF2C, MMP12, MS4A4A, MS4A6A, NLRP3, NME8, NOS2, PICALM, PILRA, PLCG2, PTK2B, SCIMP, SLC24A4, SORL1, SPI1, SPP1, SPPL2A, TBK1, TNF, TREM2, TREML2, TYROBP, and ZCWPW1.

[0013] In some embodiments, the subject is a mammal (eg, a human).

[0014] In some embodiments, the branched siRNA is administered to a subject intrathecally, intracerebroventricularly, or intrastriatally.

[0015] In some embodiments, the siRNA molecule is biantennary. In some embodiments, the siRNA molecule is triantennary. In some embodiments, the siRNA molecule is tetraantennary.

[0016] In some embodiments, the siRNA comprises (i) an antisense strand having complementarity to a portion of one or more genes selected from the group consisting of APOE, BIN1, C1QA, C3, C9ORF72, CCL5, CD33, CLU / APOJ, CR1, CXCL10, CXCL13, IFIT1, IFIT3, IFITM3, IFNAR1, IFNAR2, IL10RA, IL1A, IL1B, IL1RAP, INPP5D, ITGAM, MEF2C, MMP12, NLRP3, NOS2, PILRA, PLCG2, PTK2B, SLC24A4, TBK1, and TNF, and (ii) a sense strand having complementarity to the antisense strand.

[0017] In some embodiments, the siRNA comprises an antisense strand that has complementarity to (i) a portion of a gene encoding a positive regulator of a gene whose increased expression and / or activity (e.g., compared to the level of expression and / or activity observed in a reference subject) is associated with a disease state.

[0018] In some embodiments, the siRNA comprises an antisense strand that has complementarity to (i) a portion of a gene encoding a negative regulator of a gene whose reduced expression and / or activity (e.g., compared to the level of expression and / or activity observed in a reference subject) is associated with a disease state.

[0019] In some embodiments, the siRNA comprises an antisense strand having complementarity to a splice isoform of a gene in which (i) overexpressed splice isoforms relative to expression of a reference splice isoform are associated with a disease state.

[0020] In any of the foregoing embodiments, the siRNA can also include (ii) a sense strand that has complementarity to the antisense strand.

[0021] In some embodiments, the antisense strand has complementarity (e.g., at least 85% complementarity, e.g., 85% complementarity, 86% complementarity, 87% complementarity, 88% complementarity, 89% complementarity, 90% complementarity, 91% complementarity, 92% complementarity, 93% complementarity, 94% complementarity, 95% complementarity, 96% complementarity, 97% complementarity, 98% complementarity, 99% complementarity, or 100% complementarity) to a portion of at least 10 consecutive nucleotides of an mRNA molecule encoding one or more of the above genes. For example, the antisense strand may be selected from 10 contiguous nucleotides, 11 contiguous nucleotides, 12 contiguous nucleotides, 13 contiguous nucleotides, 14 contiguous nucleotides, 15 contiguous nucleotides, 16 contiguous nucleotides, 17 contiguous nucleotides, 18 contiguous nucleotides, 19 contiguous nucleotides, 20 contiguous nucleotides, 21 contiguous nucleotides, 22 contiguous nucleotides, 23 contiguous nucleotides, 24 contiguous nucleotides, 25 contiguous nucleotides, 26 contiguous nucleotides, 27 contiguous nucleotides, 28 contiguous nucleotides, 29 contiguous nucleotides, 30 contiguous nucleotides, 31 contiguous nucleotides, 32 contiguous nucleotides, 33 contiguous nucleotides, 34 contiguous nucleotides, 35 contiguous nucleotides, 36 contiguous nucleotides, 37 contiguous nucleotides, 38 contiguous nucleotides, 39 contiguous nucleotides, 40 contiguous nucleotides, 41 contiguous nucleotides, 42 contiguous nucleotides, 43 contiguous nucleotides, 44 contiguous nucleotides, 45 contiguous nucleotides, 46 contiguous nucleotides, 47 contiguous nucleotides, 48 ​​contiguous nucleotides, 49 contiguous nucleotides, 50 contiguous nucleotides, 51 contiguous nucleotides, 52 contiguous nucleotides, 53 contiguous nucleotides, 54 contiguous nucleotides, 55 cont In some embodiments, the complementary sequence may have complementarity to a portion of 31 contiguous nucleotides, 32 contiguous nucleotides, 33 contiguous nucleotides, 34 contiguous nucleotides, 35 contiguous nucleotides, 36 contiguous nucleotides, 37 contiguous nucleotides, 38 contiguous nucleotides, 39 contiguous nucleotides, 40 contiguous nucleotides, 41 contiguous nucleotides, 42 contiguous nucleotides, 43 contiguous nucleotides, 44 contiguous nucleotides, 45 contiguous nucleotides, 46 contiguous nucleotides, 47 contiguous nucleotides, 48 ​​contiguous nucleotides, 49 contiguous nucleotides, or 50 or more contiguous nucleotides.

[0022] In some embodiments, the antisense strand has complementarity (e.g., at least 85% complementarity, e.g., 85% complementarity, 86% complementarity, 87% complementarity, 88% complementarity, 89% complementarity, 90% complementarity, 91% complementarity, 92% complementarity, 93% complementarity, 94% complementarity, 95% complementarity, 96% complementarity, 97% complementarity, 98% complementarity, 99% complementarity, or 100% complementarity) to a portion of 10 to 50 consecutive nucleotides of an mRNA molecule encoding one or more of the above genes. For example, the antisense strand may have complementarity to a portion of 11 to 45 contiguous nucleotides, 12 to 40 contiguous nucleotides, 13 to 35 contiguous nucleotides, 14 to 30 contiguous nucleotides, 15 to 29 contiguous nucleotides, 16 to 28 contiguous nucleotides, 17 to 27 contiguous nucleotides, 18 to 26 contiguous nucleotides, or 19 to 22 contiguous nucleotides of an mRNA molecule encoding one or more of the above-mentioned genes.

[0023] In some embodiments, the antisense strand comprises, in the 5'-3' direction, a region represented by the following formula: Z-((AP-) n (BP-) m ) q wherein Z is a 5' phosphorus stabilizing moiety, each A is independently a 2'-O-methyl (2'-O-Me) ribonucleoside, each B is independently a 2'-fluororibonucleoside, each P is independently an internucleoside linkage selected from a phosphodiester linkage and a phosphorothioate linkage, n is an integer from 1 to 5 (e.g., 1, 2, 3, 4, or 5), m is an integer from 1 to 5 (e.g., 1, 2, 3, 4, or 5), and q is an integer from 1 to 15 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15).

[0024] In some embodiments, the antisense strand has a structure represented by formula AI, where in the 5'-3' direction, formula AI is: AB-(A') j -CP 2 -DP 1 -(C'-P 1 ) k -C' Formula AI where A is of the formula CP 1 -DP 1 It is expressed as Each A' has the formula CP 2 -DP 2 It is expressed as B is the formula CP 2 -DP 2 -DP 2 -DP 2 It is expressed as each C is a 2'-O-methyl (2'-O-Me) ribonucleoside; each C' is independently a 2'-O-Me ribonucleoside or a 2'-fluoro (2'-F) ribonucleoside; each D is a 2'-F ribonucleoside; Each P 1 is a phosphorothioate internucleoside linkage, Each P 2 is a phosphodiester internucleoside linkage, j is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7); k is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7).

[0025] In some embodiments, the antisense strand has a structure represented by Formula A1, which, in the 5'-3' direction, is: ASBSAOBOBOBOAOBOAOBOA-OBOAOBOAOBSASASASBSA Formula A1 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0026] In some embodiments, the antisense strand has a structure represented by Formula A-II, which, in the 5'-3' direction, is: AB-(A') j -CP 2 -DP 1 -(CP 1 ) k -C' Formula A-II where A is of the formula CP 1 -DP 1 It is expressed as Each A' has the formula CP 2 -DP 2 It is expressed as B is the formula CP 2 -DP 2 -DP 2 -DP 2 It is expressed as each C is a 2'-O-methyl (2'-O-Me) ribonucleoside; each C' is independently a 2'-O-Me ribonucleoside or a 2'-fluoro (2'-F) ribonucleoside; each D is a 2'-F ribonucleoside; Each P 1 is a phosphorothioate internucleoside linkage, Each P 2 is a phosphodiester internucleoside linkage, j is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7); k is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7).

[0027] In some embodiments, the antisense strand has a structure represented by Formula A2, which, in the 5'-3' direction, is: ASBSAOBOBOBOAOBOAOBOA-OBOAAOBOAOBSASASASASA formula A2 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0028] In some embodiments, the sense strand has a structure represented by formula S-III, which, in the 5'-3' direction, is: E-(A') m -F Formula S-III In the formula, E is a compound represented by the formula (CP 1 ) 2 It is expressed as F is the formula (CP 2 ) 3 -DP 1 -CP 1 -C, (CP 2 ) 3 -DP 2 -CP 2 -C, (CP 2 ) 3 -DP 1 -CP 1 -D, or (CP 2 ) 3 -DP 2 -CP 2 -D, A', C, D, P 1 , and P 2 is as defined in formula II, m is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7).

[0029] In some embodiments, the sense strand has a structure represented by formula S1, which, in the 5'-3' direction, is: ASASAOBOAOBOAOBOAOBOA-OAOAOBBSASA Formula S1 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0030] In some embodiments, the sense strand has a structure represented by formula S2, which, in the 5'-3' direction, is: ASASAOBOAOBOAOBOAOBOA-OAOAOBOAOA formula S2 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0031] In some embodiments, the sense strand has a structure represented by formula S3, which, in the 5'-3' direction, is: ASASAOBOAOBOAOBOAOBOA-OAOAOBSASB formula S3 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0032] In some embodiments, the sense strand has a structure represented by formula S4, which, in the 5'-3' direction, is: ASASAOBOAOBOAOBOAOBOA-OAOAOBOAOB Formula S4 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0033] In some embodiments, the antisense strand has a structure represented by Formula A-IV, which, in the 5'-3' direction, is: A-(A') j -CP 2 -B-(CP 1 ) k -C' Formula A-IV where A is of the formula CP 1 -DP 1 It is expressed as Each A' has the formula CP 2 -DP 2 It is expressed as B is the formula DP 1 -CP 1 -DP 1 It is expressed as each C is a 2'-O-Me ribonucleoside; each C' is independently a 2'-O-Me ribonucleoside or a 2'-F ribonucleoside; each D is a 2'-F ribonucleoside; Each P 1 is a phosphorothioate internucleoside linkage, Each P 2 is a phosphodiester internucleoside linkage, j is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7); k is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7).

[0034] In some embodiments, the antisense strand has a structure represented by Formula A3, which, in the 5'-3' direction, is: ASBSAOBOAOBOAOBOAOBOA-OBOAOBOAOBSASASASA formula A3 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0035] In some embodiments, the sense strand has a structure represented by formula SV, where in the 5'-3' direction, formula SV is: E-(A') m -CP 2 -F formula SV In the formula, E is a compound represented by the formula (CP 1 ) 2 It is expressed as F is the formula DP 1 -CP 1 -C,DP 2 -CP 2 -C, D.P. 1 -CP 1 -D, or DP 2 -CP 2 -D, A', C, D, P 1 , and P 2 is as defined in formula IV, m is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7).

[0036] In some embodiments, the sense strand has a structure represented by formula S5, which, in the 5'-3' direction, is: ASASAOBOAOBOAOBOAOBOA-OBOAOBSASA formula S5 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0037] In some embodiments, the sense strand has a structure represented by formula S6, which, in the 5'-3' direction, is: ASASAOBOAOBOAOBOAOBOA-OBOAOBOAOA formula S6 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0038] In some embodiments, the sense strand has a structure represented by formula S7, which, in the 5'-3' direction, is: ASASAOBOAOBOAOBOAOBOA-OBOAOBSASB formula S7 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0039] In some embodiments, the sense strand has a structure represented by formula S8, which, in the 5'-3' direction, is: ASASAOBOAOBOAOBOAOBOA-OBOAOBOAOB formula S8 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0040] In some embodiments, the antisense strand has a structure represented by Formula A-VI, which, in the 5'-3' direction, is: A.B. j -EB k -EFG l -DP 1 -C' Formula A-VI where A is of the formula CP 1 -DP 1 It is expressed as Each B is a formula C~P 2 It is expressed as each C is a 2'-O-Me ribonucleoside; each C' is independently a 2'-O-Me ribonucleoside or a 2'-F ribonucleoside; each D is a 2'-F ribonucleoside; Each E is a function of the formula DP 2 -CP 2 It is expressed as F is the formula DP 1 -CP 1 It is expressed as Each G has the formula CP 1 It is expressed as Each P 1 is a phosphorothioate internucleoside linkage, Each P 2 is a phosphodiester internucleoside linkage, j is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7); k is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7); l is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7).

[0041] In some embodiments, the antisense strand has a structure represented by Formula A4, which, in the 5'-3' direction, is: ASBSAOAOAOBOAOAOAOAOA-OAOAOBOAOBSASASASBSA formula A4 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0042] In some embodiments, the sense strand has a structure represented by formula S-VII, which, in the 5'-3' direction, is: HB m -I n -A'-B o -HC Formula S-VII where A' is a compound of the formula CP2 -DP 2 It is expressed as Each H is a function of the formula (CP 1 ) 2 It is expressed as Each I is expressed by the formula (DP 2 ), B, C, D, P 1 and P 2 is as defined in formula VI, m is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7); n is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7); o is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7).

[0043] In some embodiments, the sense strand has a structure represented by formula S9, which, in the 5'-3' direction, is: ASASAOAOAOBOBOBOAOBOA-OAOAOAASASA formula S9 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0044] In some embodiments, the antisense strand also has a 5' phosphorus stabilizing moiety at the 5' end of the antisense strand.

[0045] In some embodiments, the sense strand also has a 5' phosphorus stabilizing moiety at the 5' end of the sense strand.

[0046] In some embodiments, each 5'-phosphorus stabilizing moiety is independently any one of Formulas I-VIII: [ka] In the formula, Nuc represents a nucleobase such as adenine, uracil, guanine, thymine, or cytosine, and R represents an optionally substituted alkyl, an optionally substituted alkenyl, or an optionally substituted alkynyl (e.g., an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl), phenyl, benzyl, hydroxy, or hydrogen.

[0047] In some embodiments, Z is an (E)-vinyl phosphonate according to formula III.

[0048] In some embodiments, n is 1 to 4. In some embodiments, n is 1 to 3. In some embodiments, n is 1 to 2. In some embodiments, n is 1.

[0049] In some embodiments, m is 1 to 4. In some embodiments, m is 1 to 3. In some embodiments, m is 1 to 2. In some embodiments, m is 1.

[0050] In some embodiments, n and m are each 1.

[0051] In some embodiments, 50% or more of the ribonucleotides in the antisense strand are 2'-O-Me ribonucleotides (e.g., 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 109, 109, 102, 103, 104, 105, 106, 107, 108, 109 ... 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% can be 2'-O-Me ribonucleotides).

[0052] In some embodiments, 60% or more of the ribonucleotides in the antisense strand are 2'-O-Me ribonucleotides (e.g., 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the ribonucleotides in the antisense strand can be 2'-O-Me ribonucleotides).

[0053] In some embodiments, 70% or more of the ribonucleotides in the antisense strand are 2'-O-Me ribonucleotides (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the ribonucleotides in the antisense strand can be 2'-O-Me ribonucleotides).

[0054] In some embodiments, 80% or more of the ribonucleotides in the antisense strand are 2'-O-Me ribonucleotides (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the ribonucleotides in the antisense strand can be 2'-O-Me ribonucleotides).

[0055] In some embodiments, 90% or more of the ribonucleotides in the antisense strand are 2'-O-Me ribonucleotides (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the ribonucleotides in the antisense strand can be 2'-O-Me ribonucleotides).

[0056] In some embodiments, 10% or less of the internucleoside linkages are phosphodiester or phosphorothioate linkages, hi some embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the internucleoside linkages are phosphodiester or phosphorothioate linkages.

[0057] In some embodiments, 100% of the internucleoside linkages are phosphodiester or phosphorothioate linkages.

[0058] In some embodiments, the nine internucleoside linkages are phosphodiester or phosphorothioate linkages.

[0059] In some embodiments, the length of the antisense strand is 10 to 30 nucleotides (e.g., 10 nucleotides, 11 nucleotides, 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, or 30 nucleotides), 15 to 25 nucleotides (e.g., 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, or 25 nucleotides), or 18 to 23 nucleotides (e.g., 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, or 23 nucleotides). In some embodiments, the length of the antisense strand is 20 nucleotides. In some embodiments, the length of the antisense strand is 21 nucleotides. In some embodiments, the length of the antisense strand is 22 nucleotides. In some embodiments, the length of the antisense strand is 23 nucleotides. In some embodiments, the length of the antisense strand is 24 nucleotides. In some embodiments, the length of the antisense strand is 25 nucleotides. In some embodiments, the length of the antisense strand is 26 nucleotides. In some embodiments, the length of the antisense strand is 27 nucleotides. In some embodiments, the length of the antisense strand is 28 nucleotides. In some embodiments, the length of the antisense strand is 29 nucleotides. In some embodiments, the length of the antisense strand is 30 nucleotides.

[0060] In some embodiments, the siRNA molecules of the branched compound are linked to each other via a linker (e.g., ethylene glycol oligomer, such as tetraethylene glycol). In some embodiments, the siRNA molecules of the branched compound are linked to each other by a linker between the sense strand of one siRNA molecule and the sense strand of another siRNA molecule. In some embodiments, the siRNA molecules are linked to each other by a linker between the antisense strand of one siRNA molecule and the antisense strand of another siRNA molecule. In some embodiments, the siRNA molecules of the branched compound are linked to each other by a linker between the sense strand of one siRNA molecule and the antisense strand of another siRNA molecule.

[0061] In some embodiments, the length of the sense strand is 12 to 30 nucleotides (e.g., 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, or 30 nucleotides), 14 to 18 nucleotides (e.g., 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides). In some embodiments, the length of the sense strand is 15 nucleotides. In some embodiments, the length of the sense strand is 16 nucleotides. In some embodiments, the length of the sense strand is 17 nucleotides. In some embodiments, the length of the sense strand is 18 nucleotides. In some embodiments, the length of the sense strand is 19 nucleotides. In some embodiments, the length of the sense strand is 20 nucleotides. In some embodiments, the length of the sense strand is 21 nucleotides. In some embodiments, the length of the sense strand is 22 nucleotides. In some embodiments, the length of the sense strand is 23 nucleotides. In some embodiments, the sense strand is 24 nucleotides in length. In some embodiments, the sense strand is 25 nucleotides in length. In some embodiments, the sense strand is 26 nucleotides in length. In some embodiments, the sense strand is 27 nucleotides in length. In some embodiments, the sense strand is 28 nucleotides in length. In some embodiments, the sense strand is 29 nucleotides in length. In some embodiments, the sense strand is 30 nucleotides in length.

[0062] In some embodiments, the four internucleoside linkages are phosphorothioate linkages.

[0063] In some embodiments, the antisense strand is 18 nucleotides in length and the sense strand is 14 nucleotides in length.

[0064] In some embodiments, the antisense strand is 18 nucleotides in length and the sense strand is 15 nucleotides in length.

[0065] In some embodiments, the antisense strand is 18 nucleotides in length and the sense strand is 16 nucleotides in length.

[0066] In some embodiments, the antisense strand is 18 nucleotides in length and the sense strand is 17 nucleotides in length.

[0067] In some embodiments, the antisense strand is 18 nucleotides in length and the sense strand is 18 nucleotides in length.

[0068] In some embodiments, the antisense strand is 19 nucleotides in length and the sense strand is 14 nucleotides in length.

[0069] In some embodiments, the antisense strand is 19 nucleotides in length and the sense strand is 15 nucleotides in length.

[0070] In some embodiments, the antisense strand is 19 nucleotides in length and the sense strand is 16 nucleotides in length.

[0071] In some embodiments, the antisense strand is 19 nucleotides in length and the sense strand is 17 nucleotides in length.

[0072] In some embodiments, the antisense strand is 19 nucleotides in length and the sense strand is 18 nucleotides in length.

[0073] In some embodiments, the antisense strand is 19 nucleotides in length and the sense strand is 19 nucleotides in length.

[0074] In some embodiments, the antisense strand is 20 nucleotides in length and the sense strand is 14 nucleotides in length.

[0075] In some embodiments, the antisense strand is 20 nucleotides in length and the sense strand is 15 nucleotides in length.

[0076] In some embodiments, the antisense strand is 20 nucleotides in length and the sense strand is 16 nucleotides in length.

[0077] In some embodiments, the antisense strand is 20 nucleotides in length and the sense strand is 17 nucleotides in length.

[0078] In some embodiments, the antisense strand is 20 nucleotides in length and the sense strand is 18 nucleotides in length.

[0079] In some embodiments, the antisense strand is 20 nucleotides in length and the sense strand is 19 nucleotides in length.

[0080] In some embodiments, the antisense strand is 20 nucleotides in length and the sense strand is 20 nucleotides in length.

[0081] In some embodiments, the antisense strand is 21 nucleotides in length and the sense strand is 14 nucleotides in length.

[0082] In some embodiments, the antisense strand is 21 nucleotides in length and the sense strand is 15 nucleotides in length.

[0083] In some embodiments, the antisense strand is 21 nucleotides in length and the sense strand is 16 nucleotides in length.

[0084] In some embodiments, the antisense strand is 21 nucleotides in length and the sense strand is 17 nucleotides in length.

[0085] In some embodiments, the antisense strand is 21 nucleotides in length and the sense strand is 18 nucleotides in length.

[0086] In some embodiments, the antisense strand is 21 nucleotides in length and the sense strand is 19 nucleotides in length.

[0087] In some embodiments, the antisense strand is 21 nucleotides in length and the sense strand is 20 nucleotides in length.

[0088] In some embodiments, the antisense strand is 21 nucleotides in length and the sense strand is 21 nucleotides in length.

[0089] In some embodiments, the antisense strand is 22 nucleotides in length and the sense strand is 14 nucleotides in length.

[0090] In some embodiments, the antisense strand is 22 nucleotides in length and the sense strand is 15 nucleotides in length.

[0091] In some embodiments, the antisense strand is 22 nucleotides in length and the sense strand is 16 nucleotides in length.

[0092] In some embodiments, the antisense strand is 22 nucleotides in length and the sense strand is 17 nucleotides in length.

[0093] In some embodiments, the antisense strand is 22 nucleotides in length and the sense strand is 18 nucleotides in length.

[0094] In some embodiments, the antisense strand is 22 nucleotides in length and the sense strand is 19 nucleotides in length.

[0095] In some embodiments, the antisense strand is 22 nucleotides in length and the sense strand is 20 nucleotides in length.

[0096] In some embodiments, the antisense strand is 22 nucleotides in length and the sense strand is 21 nucleotides in length.

[0097] In some embodiments, the antisense strand is 22 nucleotides in length and the sense strand is 22 nucleotides in length.

[0098] In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is 14 nucleotides in length.

[0099] In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is 15 nucleotides in length.

[0100] In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is 16 nucleotides in length.

[0101] In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is 17 nucleotides in length.

[0102] In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is 18 nucleotides in length.

[0103] In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is 19 nucleotides in length.

[0104] In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is 20 nucleotides in length.

[0105] In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is 21 nucleotides in length.

[0106] In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is 22 nucleotides in length.

[0107] In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is 23 nucleotides in length.

[0108] In some embodiments, the antisense strand is 24 nucleotides in length and the sense strand is 14 nucleotides in length.

[0109] In some embodiments, the antisense strand is 24 nucleotides in length and the sense strand is 15 nucleotides in length.

[0110] In some embodiments, the antisense strand is 24 nucleotides in length and the sense strand is 16 nucleotides in length.

[0111] In some embodiments, the antisense strand is 24 nucleotides in length and the sense strand is 17 nucleotides in length.

[0112] In some embodiments, the antisense strand is 24 nucleotides in length and the sense strand is 18 nucleotides in length.

[0113] In some embodiments, the antisense strand is 24 nucleotides in length and the sense strand is 19 nucleotides in length.

[0114] In some embodiments, the antisense strand is 24 nucleotides in length and the sense strand is 20 nucleotides in length.

[0115] In some embodiments, the antisense strand is 24 nucleotides in length and the sense strand is 21 nucleotides in length.

[0116] In some embodiments, the antisense strand is 24 nucleotides in length and the sense strand is 22 nucleotides in length.

[0117] In some embodiments, the antisense strand is 24 nucleotides in length and the sense strand is 23 nucleotides in length.

[0118] In some embodiments, the antisense strand is 24 nucleotides in length and the sense strand is 24 nucleotides in length.

[0119] In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is 14 nucleotides in length.

[0120] In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is 15 nucleotides in length.

[0121] In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is 16 nucleotides in length.

[0122] In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is 17 nucleotides in length.

[0123] In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is 18 nucleotides in length.

[0124] In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is 19 nucleotides in length.

[0125] In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is 20 nucleotides in length.

[0126] In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is 21 nucleotides in length.

[0127] In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is 22 nucleotides in length.

[0128] In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is 23 nucleotides in length.

[0129] In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is 24 nucleotides in length.

[0130] In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is 25 nucleotides in length.

[0131] In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is 14 nucleotides in length.

[0132] In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is 15 nucleotides in length.

[0133] In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is 16 nucleotides in length.

[0134] In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is 17 nucleotides in length.

[0135] In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is 18 nucleotides in length.

[0136] In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is 19 nucleotides in length.

[0137] In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is 20 nucleotides in length.

[0138] In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is 21 nucleotides in length.

[0139] In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is 22 nucleotides in length.

[0140] In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is 23 nucleotides in length.

[0141] In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is 24 nucleotides in length.

[0142] In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is 25 nucleotides in length.

[0143] In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is 26 nucleotides in length.

[0144] In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is 14 nucleotides in length.

[0145] In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is 15 nucleotides in length.

[0146] In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is 16 nucleotides in length.

[0147] In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is 17 nucleotides in length.

[0148] In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is 18 nucleotides in length.

[0149] In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is 19 nucleotides in length.

[0150] In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is 20 nucleotides in length.

[0151] In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is 21 nucleotides in length.

[0152] In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is 22 nucleotides in length.

[0153] In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is 23 nucleotides in length.

[0154] In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is 24 nucleotides in length.

[0155] In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is 25 nucleotides in length.

[0156] In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is 26 nucleotides in length.

[0157] In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is 27 nucleotides in length.

[0158] In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is 14 nucleotides in length.

[0159] In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is 15 nucleotides in length.

[0160] In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is 16 nucleotides in length.

[0161] In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is 17 nucleotides in length.

[0162] In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is 18 nucleotides in length.

[0163] In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is 19 nucleotides in length.

[0164] In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is 20 nucleotides in length.

[0165] In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is 21 nucleotides in length.

[0166] In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is 22 nucleotides in length.

[0167] In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is 23 nucleotides in length.

[0168] In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is 24 nucleotides in length.

[0169] In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is 25 nucleotides in length.

[0170] In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is 26 nucleotides in length.

[0171] In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is 27 nucleotides in length.

[0172] In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is 28 nucleotides in length.

[0173] In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is 14 nucleotides in length.

[0174] In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is 15 nucleotides in length.

[0175] In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is 16 nucleotides in length.

[0176] In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is 17 nucleotides in length.

[0177] In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is 18 nucleotides in length.

[0178] In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is 19 nucleotides in length.

[0179] In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is 20 nucleotides in length.

[0180] In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is 21 nucleotides in length.

[0181] In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is 22 nucleotides in length.

[0182] In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is 23 nucleotides in length.

[0183] In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is 24 nucleotides in length.

[0184] In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is 25 nucleotides in length.

[0185] In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is 26 nucleotides in length.

[0186] In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is 27 nucleotides in length.

[0187] In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is 28 nucleotides in length.

[0188] In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is 29 nucleotides in length.

[0189] In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is 14 nucleotides in length.

[0190] In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is 15 nucleotides in length.

[0191] In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is 16 nucleotides in length.

[0192] In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is 17 nucleotides in length.

[0193] In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is 18 nucleotides in length.

[0194] In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is 19 nucleotides in length.

[0195] In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is 20 nucleotides in length.

[0196] In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is 21 nucleotides in length.

[0197] In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is 22 nucleotides in length.

[0198] In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is 23 nucleotides in length.

[0199] In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is 24 nucleotides in length.

[0200] In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is 25 nucleotides in length.

[0201] In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is 26 nucleotides in length.

[0202] In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is 27 nucleotides in length.

[0203] In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is 28 nucleotides in length.

[0204] In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is 29 nucleotides in length.

[0205] In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is 30 nucleotides in length.

[0206] In another aspect, the invention features a branched siRNA molecule comprising a sense strand and an antisense strand, wherein the antisense strand comprises a region having complementarity to a segment of consecutive nucleotides in a gene selected from the group consisting of APOE, BIN1, C1QA, C3, C9ORF72, CCL5, CD33, CLU / APOJ, CR1, CXCL10, CXCL13, IFIT1, IFIT3, IFITM3, IFNAR1, IFNAR2, IL10RA, IL1A, IL1B, IL1RAP, INPP5D, ITGAM, MEF2C, MMP12, NLRP3, NOS2, PILRA, PLCG2, PTK2B, SLC24A4, TBK1, and TNF.

[0207] In some embodiments, the antisense strand has complementarity to a portion of a gene encoding a positive regulator of a gene whose increased expression and / or activity is associated with a disease state compared to the level of expression and / or activity observed in a reference subject.

[0208] In some embodiments, the antisense strand has complementarity to a portion of a gene encoding a negative regulator of a gene whose reduced expression and / or activity, relative to the level of expression and / or activity observed in a reference subject, is associated with a disease state.

[0209] In some embodiments, the antisense strand has complementarity to a splice isoform of a gene under which overexpressed splice isoforms relative to expression of a reference splice isoform are associated with a disease state.

[0210] In some embodiments, the sense strand has complementarity to the antisense strand.

[0211] In some embodiments, the siRNA molecule is biantennary. In some embodiments, the siRNA molecule is triantennary. In some embodiments, the siRNA molecule is tetraantennary.

[0212] In some embodiments, the antisense strand of the branched siRNA has, in the 5'-3' direction, the following formula: Z-((AP-) n (BP-) m ) q wherein Z is a 5' phosphorus stabilizing moiety, each A is independently a 2'-O-Me ribonucleoside, each B is independently a 2'-fluoro ribonucleoside, each P is independently an internucleoside linkage selected from a phosphodiester linkage and a phosphorothioate linkage, n is an integer from 1 to 5 (e.g., 1, 2, 3, 4, or 5), m is an integer from 1 to 5 (e.g., 1, 2, 3, 4, or 5), and q is an integer from 1 to 15 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15).

[0213] In some embodiments, the antisense strand has a structure represented by formula AI, where in the 5'-3' direction, formula AI is: AB-(A') j -CP 2 -DP 1 -(C'-P 1 ) k -C' Formula AI where A is of the formula CP 1 -DP 1 It is expressed as Each A' has the formula CP 2 -DP 2 It is expressed as B is the formula CP 2 -DP 2 -DP 2 -DP 2 It is expressed as each C is a 2'-O-methyl (2'-O-Me) ribonucleoside; each C' is independently a 2'-O-Me ribonucleoside or a 2'-fluoro (2'-F) ribonucleoside; each D is a 2'-F ribonucleoside; Each P 1 is a phosphorothioate internucleoside linkage, Each P 2 is a phosphodiester internucleoside linkage, j is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7); k is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7).

[0214] In some embodiments, the antisense strand has a structure represented by Formula A1, which, in the 5'-3' direction, is: ASBSAOBOBOBOAOBOAOBOA-OBOAOBOAOBSASASASBSA Formula A1 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0215] In some embodiments, the antisense strand has a structure represented by Formula A-II, which, in the 5'-3' direction, is: AB-(A') j -CP 2 -DP 1 -(CP 1 ) k -C' Formula A-II where A is of the formula CP 1 -DP 1 It is expressed as Each A' has the formula CP 2 -DP 2 It is expressed as B is the formula CP 2 -DP 2 -DP 2 -DP 2 It is expressed as each C is a 2'-O-methyl (2'-O-Me) ribonucleoside; each C' is independently a 2'-O-Me ribonucleoside or a 2'-fluoro (2'-F) ribonucleoside; each D is a 2'-F ribonucleoside; Each P 1 is a phosphorothioate internucleoside linkage, Each P 2 is a phosphodiester internucleoside linkage, j is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7); k is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7).

[0216] In some embodiments, the antisense strand has a structure represented by Formula A2, which, in the 5'-3' direction, is: ASBSAOBOBOBOAOBOAOBOA-OBOAAOBOAOBSASASASASA formula A2 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0217] In some embodiments, the sense strand has a structure represented by formula S-III, which, in the 5'-3' direction, is: E-(A') m -F Formula S-III In the formula, E is a compound represented by the formula (CP 1 ) 2 It is expressed as F is the formula (CP 2 ) 3 -DP 1-CP 1 -C, (CP 2 ) 3 -DP 2 -CP 2 -C, (CP 2 ) 3 -DP 1 -CP 1 -D, or (CP 2 ) 3 -DP 2 -CP 2 -D, A', C, D, P 1 , and P 2 is as defined in formula II, m is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7).

[0218] In some embodiments, the sense strand has a structure represented by formula S1, which, in the 5'-3' direction, is: ASASAOBOAOBOAOBOAOBOA-OAOAOBBSASA Formula S1 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0219] In some embodiments, the sense strand has a structure represented by formula S2, which, in the 5'-3' direction, is: ASASAOBOAOBOAOBOAOBOA-OAOAOBOAOA formula S2 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0220] In some embodiments, the sense strand has a structure represented by formula S3, which, in the 5'-3' direction, is: ASASAOBOAOBOAOBOAOBOA-OAOAOBSASB formula S3 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0221] In some embodiments, the sense strand has a structure represented by formula S4, which, in the 5'-3' direction, is: ASASAOBOAOBOAOBOAOBOA-OAOAOBOAOB Formula S4 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0222] In some embodiments, the antisense strand has a structure represented by Formula A-IV, which, in the 5'-3' direction, is: A-(A') j -CP 2 -B-(CP 1 ) k -C' Formula A-IV where A is of the formula CP 1 -DP 1 It is expressed as Each A' has the formula CP 2 -DP 2 It is expressed as B is the formula DP 1 -CP 1 -DP 1 It is expressed as each C is a 2'-O-Me ribonucleoside; each C' is independently a 2'-O-Me ribonucleoside or a 2'-F ribonucleoside; each D is a 2'-F ribonucleoside; Each P 1 is a phosphorothioate internucleoside linkage, Each P 2 is a phosphodiester internucleoside linkage, j is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7); k is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7).

[0223] In some embodiments, the antisense strand has a structure represented by Formula A3, which, in the 5'-3' direction, is: ASBSAOBOAOBOAOBOAOBOA-OBOAOBOAOBSASASASA formula A3 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0224] In some embodiments, the sense strand has a structure represented by formula SV, where in the 5'-3' direction, formula SV is: E-(A') m -CP 2 -F formula SV In the formula, E is a compound represented by the formula (CP 1 ) 2 It is expressed as F is the formula DP 1 -CP 1 -C, D.P. 2 -CP 2 -C, D.P. 1 -CP 1 -D, or DP 2 -CP 2 -D, A', C, D, P1 , and P 2 is as defined in formula IV, m is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7).

[0225] In some embodiments, the sense strand has a structure represented by formula S5, which, in the 5'-3' direction, is: ASASAOBOAOBOAOBOAOBOA-OBOAOBSASA formula S5 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0226] In some embodiments, the sense strand has a structure represented by formula S6, which, in the 5'-3' direction, is: ASASAOBOAOBOAOBOAOBOA-OBOAOBOAOA formula S6 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0227] In some embodiments, the sense strand has a structure represented by formula S7, which, in the 5'-3' direction, is: ASASAOBOAOBOAOBOAOBOA-OBOAOBSASB formula S7 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0228] In some embodiments, the sense strand has a structure represented by formula S8, which, in the 5'-3' direction, is: ASASAOBOAOBOAOBOAOBOA-OBOAOBOAOB formula S8 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0229] In some embodiments, the antisense strand has a structure represented by Formula A-VI, which, in the 5'-3' direction, is: A.B. j -EB k -EFG l -DP 1 -C' Formula A-VI where A is of the formula CP 1 -DP 1 It is expressed as Each B is a function of the formula CP 2 It is expressed as each C is a 2'-O-Me ribonucleoside; each C' is independently a 2'-O-Me ribonucleoside or a 2'-F ribonucleoside; each D is a 2'-F ribonucleoside; Each E is a function of the formula DP 2 -CP 2 It is expressed as F is the formula DP 1 -CP 1 It is expressed as Each G has the formula CP 1 It is expressed as Each P 1 is a phosphorothioate internucleoside linkage, Each P 2 is a phosphodiester internucleoside linkage, j is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7); k is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7); l is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7).

[0230] In some embodiments, the antisense strand has a structure represented by Formula A4, which, in the 5'-3' direction, is: ASBSAOAOAOBOAOAOAOAOA-OAOAOBOAOBSASASASBSA formula A4 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0231] In some embodiments, the sense strand has a structure represented by formula S-VII, which, in the 5'-3' direction, is: HB m -I n -A'-B o -HC Formula S-VII where A' is a compound of the formula CP 2 -DP 2 It is expressed as Each H is a function of the formula (CP 1 ) 2 It is expressed as Each I is expressed by the formula (DP 2 ), B, C, D, P 1 and P 2 is as defined in formula VI, m is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7); n is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7); o is an integer from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7).

[0232] In some embodiments, the sense strand has a structure represented by formula S9, which, in the 5'-3' direction, is: ASASAOAOAOBOBOBOAOBOA-OAOAOAASASA formula S9 wherein A represents a 2'-O-Me ribonucleoside, B represents a 2'-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

[0233] In some embodiments, the antisense strand also has a 5' phosphorus stabilizing moiety at the 5' end of the antisense strand.

[0234] In some embodiments, the sense strand also has a 5' phosphorus stabilizing moiety at the 5' end of the sense strand.

[0235] In some embodiments, each 5' phosphorus stabilizing moiety is independently represented by any one of Formulas I-VIII: [ka] In the formula, Nuc represents a nucleobase such as adenine, uracil, guanine, thymine, or cytosine, and R represents an optionally substituted alkyl, an optionally substituted alkenyl, or an optionally substituted alkynyl (e.g., an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl), phenyl, benzyl, hydroxy, or hydrogen.

[0236] In some embodiments, Z is an (E)-vinyl phosphonate according to formula III.

[0237] In some embodiments, each P is independently selected from phosphodiester and phosphorothioate.

[0238] In some embodiments, n is 1 to 4 (e.g., 1, 2, 3, or 4), 1 to 3 (e.g., 1, 2, or 3), or 1 to 2. In some embodiments, n is 1.

[0239] In some embodiments, m is 1 to 4 (e.g., 1, 2, 3, or 4), 1 to 3 (e.g., 1, 2, or 3), or 1 to 2. In some embodiments, m is 1.

[0240] In some embodiments, n and m are each 1.

[0241] In some embodiments, 50% or more of the ribonucleotides in the antisense strand are 2'-O-Me ribonucleotides (e.g., 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 109, 109, 102, 103, 104, 105, 106, 107, 108, 109 ... 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% can be 2'-O-Me ribonucleotides).

[0242] In some embodiments, 60% or more of the ribonucleotides in the antisense strand are 2'-O-Me ribonucleotides (e.g., 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the ribonucleotides in the antisense strand can be 2'-O-Me ribonucleotides).

[0243] In some embodiments, 70% or more of the ribonucleotides in the antisense strand are 2'-O-Me ribonucleotides (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the ribonucleotides in the antisense strand can be 2'-O-Me ribonucleotides).

[0244] In some embodiments, 80% or more of the ribonucleotides in the antisense strand are 2'-O-Me ribonucleotides (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the ribonucleotides in the antisense strand can be 2'-O-Me ribonucleotides).

[0245] In some embodiments, 90% or more of the ribonucleotides in the antisense strand are 2'-O-Me ribonucleotides (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the ribonucleotides in the antisense strand can be 2'-O-Me ribonucleotides).

[0246] In some embodiments, 10% or less of the internucleoside linkages are phosphodiester or phosphorothioate. In some embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the internucleoside linkages are phosphodiester or phosphorothioate. In some embodiments, 100% of the internucleoside linkages are phosphodiester or phosphorothioate.

[0247] In some embodiments, the length of the antisense strand is 10 to 30 nucleotides (e.g., 10 nucleotides, 11 nucleotides, 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, or 30 nucleotides), 15 to 25 nucleotides (e.g., 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, or 25 nucleotides), or 18 to 23 nucleotides (e.g., 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, or 23 nucleotides). In some embodiments, the length of the antisense strand is 21 nucleotides. In some embodiments, the length of the antisense strand is 22 nucleotides. In some embodiments, the length of the antisense strand is 23 nucleotides. In some embodiments, the length of the antisense strand is 24 nucleotides. In some embodiments, the length of the antisense strand is 25 nucleotides. In some embodiments, the length of the antisense strand is 26 nucleotides. In some embodiments, the length of the antisense strand is 27 nucleotides. In some embodiments, the length of the antisense strand is 28 nucleotides. In some embodiments, the length of the antisense strand is 29 nucleotides. In some embodiments, the length of the antisense strand is 30 nucleotides.

[0248] In some embodiments, the nine internucleoside linkages are phosphorothioate.

[0249] In some embodiments, the sense strand of the branched siRNA has, in the 5'-3' direction, the formula: Y-((AP-) n (BP-)m ) q L-((BP-) m (AP-) n ) q wherein Y is a hydrophobic moiety (e.g., cholesterol, vitamin D, or tocopherol), L is a linker, each A is independently a 2'-O-Me ribonucleoside, each B is independently a 2'-fluororibonucleoside, each P is independently an internucleoside linkage selected from a phosphodiester linkage and a phosphorothioate linkage, n is an integer from 1 to 5 (1, 2, 3, 4, or 5), m is an integer from 1 to 5 (1, 2, 3, 4, or 5), and q is an integer from 1 to 15 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15).

[0250] In some embodiments, Y is cholesterol.

[0251] In some embodiments, Y is tocopherol.

[0252] In some embodiments, L is an ethylene glycol oligomer.

[0253] In some embodiments, L is tetraethylene glycol.

[0254] In some embodiments, each P is independently selected from phosphodiester and phosphorothioate.

[0255] In some embodiments, n is 1 to 4 (e.g., 1, 2, 3, or 4), 1 to 3 (e.g., 1, 2, or 3), or 1 to 2. In some embodiments, n is 1.

[0256] In some embodiments, m is 1 to 4 (e.g., 1, 2, 3, or 4), 1 to 3 (e.g., 1, 2, or 3), or 1 to 2. In some embodiments, m is 1.

[0257] In some embodiments, n and m are each 1.

[0258] In some embodiments, no more than 10% of the ribonucleosides are 2'-O-Me ribonucleosides.

[0259] In some embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the ribonucleosides are 2'-O-Me ribonucleosides.

[0260] In some embodiments, 10% or less of the internucleoside linkages are phosphodiester or phosphorothioate linkages. In some embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the internucleoside linkages are phosphodiester or phosphorothioate linkages. In some embodiments, 100% of the internucleoside linkages are phosphodiester or phosphorothioate linkages.

[0261] In some embodiments, the length of the sense strand is 12 to 30 nucleotides (e.g., 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, or 30 nucleotides), 14 to 18 nucleotides (e.g., 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides). In some embodiments, the length of the sense strand is 16 nucleotides. In some embodiments, the length of the sense strand is 17 nucleotides. In some embodiments, the length of the sense strand is 18 nucleotides. In some embodiments, the length of the sense strand is 19 nucleotides. In some embodiments, the length of the sense strand is 20 nucleotides. In some embodiments, the length of the sense strand is 21 nucleotides. In some embodiments, the length of the sense strand is 22 nucleotides. In some embodiments, the length of the sense strand is 23 nucleotides. In some embodiments, the length of the sense strand is 24 nucleotides. In some embodiments, the sense strand is 25 nucleotides in length. In some embodiments, the sense strand is 26 nucleotides in length. In some embodiments, the sense strand is 27 nucleotides in length. In some embodiments, the sense strand is 28 nucleotides in length. In some embodiments, the sense strand is 29 nucleotides in length. In some embodiments, the sense strand is 30 nucleotides in length.

[0262] In some embodiments, the four internucleoside linkages are phosphorothioate.

[0263] In another aspect, the invention features a method of treating a subject diagnosed with a disease associated with dysregulated microglial gene expression (e.g., a wild-type or mutant microglial gene), the method comprising administering to the subject a branched siRNA molecule described in any one of the above aspects or embodiments.

[0264] In some embodiments, the dysregulated microglial genes are ABCA7, ABI3, ADAM10, APOC1, APOE, AXL, BIN1, C1QA, C3, C9ORF72, CASS4, CCL5, CD2AP, CD33, CD68, CLPTM1, CLU, CR1, CSF1, CST7, CTSB, CTSD, CTSL, CXCL10, CXCL13, DSG2, ECHDC3, EPHA1, FABP5, FERMT2, FTH1, GNAS, GRN, HBEGF, HLA-DRB1, HLA-DRB5, IFIT1, I Selected from the group consisting of FIT3, IFITM3, IFNAR1, IFNAR2, IGF1, IL10RA, IL1A, IL1B, IL1RAP, INPP5D, ITGAM, ITGAX, LILRB4, LPL, MEF2C, MMP12, MS4A4A, MS4A6A, NLRP3, NME8, NOS2, PICALM, PILRA, PLCG2, PTK2B, SCIMP, SLC24A4, SORL1, SPI1, SPP1, SPPL2A, TBK1, TNF, TREM2, TREML2, TYROBP, and ZCWPW1.

[0265] In some embodiments, a dysregulated microglial gene exhibits increased expression and / or activity in microglial cells of a subject compared to the expression and / or activity of the same gene in microglial cells of a reference subject.

[0266] In some embodiments, a dysregulated microglial gene exhibits reduced expression and / or activity in microglial cells of a subject compared to the expression and / or activity of the same gene in microglial cells of a reference subject.

[0267] In some embodiments, administering the branched siRNA molecule to a subject results in gene silencing in the subject.

[0268] In some embodiments, gene silencing comprises silencing of any one of the genes selected from the group consisting of APOE, BIN1, C1QA, C3, C9ORF72, CCL5, CD33, CLU / APOJ, CR1, CXCL10, CXCL13, IFIT1, IFIT3, IFITM3, IFNAR1, IFNAR2, IL10RA, IL1A, IL1B, IL1RAP, INPP5D, ITGAM, MEF2C, MMP12, NLRP3, NOS2, PILRA, PLCG2, PTK2B, SLC24A4, TBK1, and TNF.

[0269] In some embodiments, gene silencing includes silencing of a positive regulator of a gene whose increased expression and / or activity is associated with a disease state compared to the level of expression and / or activity observed in a reference subject.

[0270] In some embodiments, gene silencing includes silencing of a negative regulator of a gene whose reduced expression and / or activity relative to the level of expression and / or activity observed in a reference subject is associated with a disease state.

[0271] In some embodiments, gene silencing comprises silencing a splice isoform of a gene for which overexpressed splice isoforms are associated with a disease state relative to expression of the splice isoform in a reference subject.

[0272] In some embodiments, the subject is a human. [Brief description of the drawings]

[0273] [Figure 1A]Figure 1 is a series of fluorescence images of brain and spinal cord tissues from cynomolgus monkeys treated with a single intrathecal injection of Cy3-labeled di-siRNA of the present disclosure. Fluorescence images were acquired from representative regions of the brain, including the cortex. Microglial cells (Iba1 channel), di-siRNA (Cy3 channel), and cell nuclei (DAPI) were labeled. White arrows indicate co-localization of Cy3-di-siRNA signal within microglial cells labeled with Iba1 antibody. Scale bar = 20 μm. [Figure 1B] Figure 1 is a series of fluorescence images of brain and spinal cord tissues from cynomolgus monkeys treated with a single intrathecal injection of Cy3-labeled di-siRNA of the present disclosure. Fluorescence images were acquired from representative regions of the brain, including the hippocampus. Microglial cells (Iba1 channel), di-siRNA (Cy3 channel), and cell nuclei (DAPI) were labeled. White arrows indicate co-localization of Cy3-di-siRNA signal within microglial cells labeled with Iba1 antibody. Scale bar = 20 μm. [Figure 1C] 1 is a series of fluorescence images of brain and spinal cord tissues from cynomolgus monkeys treated with a single intrathecal injection of Cy3-labeled di-siRNA of the present disclosure. Fluorescence images were acquired from representative regions of the brain, including the caudate nucleus. Microglial cells (Iba1 channel), di-siRNA (Cy3 channel), and cell nuclei (DAPI) were labeled. White arrows indicate co-localization of Cy3-di-siRNA signal within microglial cells labeled with Iba1 antibody. Scale bar = 20 μm. [Figure 1D] Figure 1 is a series of fluorescence images of brain and spinal cord tissues from cynomolgus monkeys treated with a single intrathecal injection of Cy3-labeled di-siRNA of the present disclosure. Fluorescence images were taken from representative regions of the brain, including the spinal cord. Microglial cells (Iba1 channel), di-siRNA (Cy3 channel), and cell nuclei (DAPI) were labeled. White arrows indicate co-localization of Cy3-di-siRNA signal within microglial cells labeled with Iba1 antibody. Scale bar = 20 μm. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0274] definition Unless otherwise defined herein, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. In case of any potential ambiguity, the definitions provided herein take precedence over any dictionary or extrinsic definitions. Unless otherwise required by context, singular terms shall include the plural and plural terms shall include the singular. The use of "or" means "and / or" unless otherwise specified. The use of the term "including" as well as other forms such as "includes" and "included" is not limiting.

[0275] As used herein, the term "nucleic acid" refers to an RNA or DNA molecule that is composed of a chain of ribonucleotides or deoxyribonucleotides, respectively.As used herein, the term "therapeutic nucleic acid" refers to a nucleic acid molecule (e.g., ribonucleic acid) that has partial or complete complementarity with a disease-related target mRNA, interacts with the disease-related target mRNA, and mediates the silencing of the expression of the mRNA.

[0276] As used herein, the term "carrier nucleic acid" refers to a nucleic acid molecule (e.g., a ribonucleic acid) that has sequence complementarity with and hybridizes to a therapeutic nucleic acid. As used herein, the term "3' end" refers to the end of a nucleic acid that contains an unmodified hydroxyl group at the 3' carbon of the ribose ring.

[0277] As used herein, the term "nucleoside" refers to a molecule that consists of a heterocyclic base and its sugar.

[0278] As used herein, the term "nucleotide" refers to a nucleoside having a phosphate group on its 3' or 5' sugar hydroxyl group.

[0279] As used herein, the term "siRNA" refers to small interfering RNA duplexes that induce the RNA interference (RNAi) pathway. siRNA molecules may be of various lengths (generally 18-30 base pairs) and may contain various degrees of complementarity to their target mRNA. The term "siRNA" includes duplexes of two separate strands, and single strands that optionally form a hairpin structure containing a double-stranded region.

[0280] As used herein, the term "antisense strand" refers to the strand of the siRNA duplex that contains a degree of complementarity to a target gene.

[0281] As used herein, the term "sense strand" refers to the siRNA duplex that contains complementarity to the antisense strand.

[0282] As used herein, the term "chemically modified nucleotide" or "nucleotide analog" or "altered nucleotide" or "modified nucleotide" refers to a non-standard nucleotide, including non-naturally occurring ribonucleotides or deoxyribonucleotides. Exemplary nucleotide analogs are modified at any position to alter certain chemical properties of the nucleotide while retaining the ability of the nucleotide analog to perform its intended function.

[0283] As used herein, the term "metabolically stabilized" refers to an RNA molecule that contains ribonucleotides that have been chemically modified from a 2'-hydroxyl group to a 2'-O-methyl group.

[0284] As used herein, the term "phosphorothioate" refers to a phosphate group of a nucleotide that is modified by replacing one or more of the oxygens of the phosphate group with sulfur.

[0285] As used herein, the term "ethylene glycol chain" refers to a group of the formula ((CH 2 OH) 2 ) refers to a carbon chain having

[0286] As used herein, "alkyl" refers to a saturated hydrocarbon group. Alkyl groups can be acyclic or cyclic and, if unsubstituted, contain only C and H. When naming an alkyl residue with a specific number of carbons, all geometric isomers with that number of carbons are intended to be encompassed and described. Thus, for example, "butyl" is meant to include n-butyl, sec-butyl, and iso-butyl. Examples of alkyl include ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. In some embodiments, alkyl can be substituted. Suitable substituents that can be introduced into alkyl groups include, for example, hydroxy, alkoxy, amino, alkylamino, and halo, among others.

[0287] As used herein, "alkenyl" refers to an acyclic or cyclic unsaturated hydrocarbon group having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C). Alkenyl groups, when unsubstituted, contain only C and H. When an alkenyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed and described. Thus, for example, "butenyl" is meant to include n-butenyl, sec-butenyl, and iso-butenyl. Examples of alkenyl include -CH=CH 2 , -CH 2 -CH=CH 2 , and -CH 2 -CH=CH-CH=CH 2 In some embodiments, alkenyl can be substituted. Suitable substituents that can be introduced into alkenyl groups include, for example, hydroxy, alkoxy, amino, alkylamino, and halo, among others.

[0288] As used herein, "alkynyl" refers to an acyclic or cyclic unsaturated hydrocarbon group having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C). Alkynyl groups, when unsubstituted, contain only C and H. When an alkynyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed and described. Thus, for example, "pentynyl" is meant to include n-pentynyl, sec-pentynyl, and iso-pentynyl. Examples of alkynyl include -C≡CH and -C≡C-CH 3 In some embodiments, alkynyl can be substituted. Suitable substituents that can be introduced into alkynyl groups include, for example, hydroxy, alkoxy, amino, alkylamino, and halo, among others.

[0289] As used herein, the term "phenyl" refers to a monocyclic arene having one hydrogen atom removed from a carbon atom of the ring. A phenyl group can be unsubstituted or substituted with one or more suitable substituents, which substitute for the H of the phenyl group.

[0290] As used herein, the term "benzyl" refers to the monovalent radical obtained when the hydrogen atom attached to the methyl group of toluene is removed. Benzyl is commonly represented by the phenyl-CH 2 -. A benzyl group can be unsubstituted or substituted with one or more suitable substituents. For example, the substituents can be H and / or methylene (-CH) on the phenyl component. 2 -) may replace H in the component.

[0291] As used herein, the term "amide" refers to an alkyl or aromatic group bound to an amino-carbonyl functional group.

[0292] As used herein, the terms "internucleoside" and "internucleotide" refer to a bond between nucleosides and between nucleotides, respectively.

[0293] As used herein, the term “triazole” refers to a compound of the formula (C) having a five-membered ring of two carbons and three nitrogens, the positions of which can vary to give rise to multiple isomers. 2 H 3 N 3 ) refers to a heterocyclic compound having the formula:

[0294] As used herein, the term "end group" refers to the group at which a carbon chain or nucleic acid ends.

[0295] As used herein, the term "lipophilic amino acid" refers to an amino acid that contains a hydrophobic moiety (eg, an alkyl chain or an aromatic ring).

[0296] As used herein, the term "antagomir" refers to a nucleic acid that can function as an inhibitor of miRNA activity.

[0297] As used herein, the term "gapmer" refers to a chimeric antisense nucleic acid that contains a central block of deoxynucleotide monomers of sufficient length to induce RNase H cleavage. The deoxynucleotide block is flanked by ribonucleotide monomers or ribonucleotide monomers containing modifications.

[0298] As used herein, the term "mixmer" refers to a nucleic acid composed of a mixture of locked nucleic acid (LNA) and DNA.

[0299] As used herein, the term "guide RNA" refers to a nucleic acid that has sequence complementarity to a specific sequence in a genome immediately upstream or one base pair upstream of a protospacer adjacent motif (PAM) sequence used in the CRISPR / Cas9 gene editing system. Alternatively, "guide RNA" may refer to a nucleic acid that has sequence complementarity (e.g., is antisense) to a specific messenger RNA (mRNA) sequence. In this context, a guide RNA may also have sequence complementarity to a "passenger RNA" sequence of equal or shorter length that is identical or substantially identical to the sequence of the mRNA to which the guide RNA hybridizes.

[0300] As used herein, the term "delivery target" refers to an organ or part of the body to which it is desired to deliver a branched oligonucleotide composition.

[0301] As used herein, the term "branched siRNA" refers to a compound that contains two or more double-stranded siRNA molecules that are covalently linked to each other.Branched siRNA molecules can be "bi-branched", also referred to herein as "di-siRNA", where the siRNA molecule comprises two siRNA molecules that are covalently linked to each other, for example, via a linker.Branched siRNA molecules can be "tri-branched", also referred to herein as "tri-siRNA", where the siRNA molecule comprises three siRNA molecules that are covalently linked to each other, for example, via a linker.Branched siRNA molecules can be "four-branched", also referred to herein as "tetra-siRNA", where the siRNA molecule comprises four siRNA molecules that are covalently linked to each other, for example, via a linker.

[0302] As used herein, the term "5' phosphorus stabilizing moiety" refers to a terminal phosphate group, including phosphate as well as modified phosphates (e.g., phosphorothioates, phosphodiesters, phosphonates). The phosphate moiety may be located at either terminus, but is preferred at the 5' terminal nucleoside. In one aspect, the terminal phosphate is unmodified having the formula -OP(=O)(OH)OH. In another aspect, the terminal phosphate is modified such that one or more of the O and OH groups are replaced with H, O, S, N(R'), or an alkyl, amino protecting group, or unsubstituted or substituted alkyl where R' is H. In some embodiments, the 5' and or 3' terminal groups can each independently comprise one to three phosphate moieties that are unmodified (diphosphate or triphosphate) or modified.

[0303] As used herein, the term "from X to Y" is inclusive of values ​​of X and Y. For example, "from X to Y" refers to a range of values ​​between a value of X and a value of Y, as well as a value of X and a value of Y.

[0304] As used herein, "amino acid" refers to a molecule that contains an amine and a carboxyl functional group, with the side chain characteristic of the amino acid.

[0305] In some embodiments, the amino acid is selected from the group of proteinogenic amino acids. In other embodiments, the amino acid is an L-amino acid or a D-amino acid. In other embodiments, the amino acid is a synthetic amino acid (e.g., a beta-amino acid).

[0306] For example, certain internucleotide linkages provided herein, including phosphodiesters and phosphorothioates, contain a formal charge of −1 at physiological pH, which is understood to be balanced by a cationic moiety, e.g., an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or magnesium, or an ammonium or guanidinium ion.

[0307] The phosphate group of the nucleotide may also be modified, for example, by replacing one or more of the oxygens of the phosphate group with sulfur (e.g., phosphorothioates), or by making other substitutions which enable the nucleotide to perform its intended function, as described, for example, in Eckstein, Antisense Nucleic Acid Drug Dev. 2000 Apr. 10(2): 117-21; Rusckowski et al. Antisense Nucleic Acid Drug Dev. 2000 Oct. 10(5): 333-45; Stein, Antisense Nucleic Acid Drug Dev. 2001 Oct. 11(5): 317-25; Vorobjev et al. Antisense Nucleic Acid Drug Dev. 2001 Apr. 11(2): 77-85; and US Pat. No. 5,684,143. Certain of the above-referenced modifications (eg, phosphate group modifications) preferably reduce the rate of hydrolysis in vivo or in vitro of, for example, polynucleotides that contain the aforementioned analogs.

[0308] As used herein, the term "complementary" refers to two nucleotides that form a canonical Watson-Crick base pair. For the avoidance of doubt, in the context of the present disclosure, Watson-Crick base pairs include adenine-thymine, adenine-uracil, and cytosine-guanine base pairs. In this context, proper Watson-Crick base pairs are referred to as "matches," while each unpaired nucleotide and improperly paired nucleotides are referred to as "mismatches." Alignment for purposes of determining nucleic acid sequence complementarity percentages can be accomplished in a variety of ways within the capabilities of one of skill in the art, using publicly available computer software, such as, for example, BLAST, BLAST-2, or Megalign software.

[0309] As used herein, the term "percent sequence complementarity" to a reference polynucleotide sequence is defined as the percent of nucleic acids in a candidate sequence that are complementary to nucleic acids in the reference polynucleotide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence complementarity. A given nucleotide is considered to be "complementary" to a reference nucleotide as described herein if the two nucleotides form a standard Watson-Crick base pair. For the avoidance of doubt, in the context of the present disclosure, Watson-Crick base pairs include adenine-thymine, adenine-uracil, and cytosine-guanine base pairs. In this context, a proper Watson-Crick base pair is referred to as a "match," while each unpaired nucleotide and an improperly paired nucleotide are referred to as a "mismatch." Alignment for purposes of measuring nucleic acid sequence complementarity percentages can be accomplished in a variety of ways within the capabilities of one of skill in the art, using publicly available computer software, such as, for example, BLAST, BLAST-2, or Megalign software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms necessary to achieve maximum complementarity over the entire length of the sequences being compared. By way of illustration, the percentage of sequence complementarity of a given nucleic acid sequence A to a given nucleic acid sequence B (which can alternatively be referred to as a given nucleic acid sequence A having a particular percentage of complementarity to a given nucleic acid sequence B) is calculated as follows: 100×(fraction X / Y) where X is the number of complementary base pairs in a program alignment of A and B (e.g., as performed by computer software such as BLAST) and Y is the total number of nucleic acids in B. It is understood that if the length of nucleic acid sequence A is not equal to the length of nucleic acid sequence B, then the percent sequence complementarity to B is not equal to the percent sequence complementarity of B to A. As used herein, a query nucleic acid sequence is considered to be "fully complementary" to a reference nucleic acid sequence if the query nucleic acid sequence has 100% sequence complementarity to the reference nucleic acid sequence.

[0310] The term "gene silencing" refers to the suppression of gene expression, for example, transgene, heterologous gene and / or endogenous gene expression, which can be mediated through the process of affecting transcription and / or the process of affecting post-transcriptional mechanisms.In some embodiments, gene silencing occurs when RNAi molecules initiate the inhibition or degradation of the mRNA transcribed from a gene of interest in a sequence-specific manner through RNA interference, thereby preventing the translation of the gene's product.

[0311] As used herein, the term "overactive disease driver gene" refers to a microglial gene that has increased activity and / or expression that contributes to or causes a disease state in a subject (e.g., a human). The disease state may be caused or exacerbated by the overactive disease driver gene directly or through an intermediary gene(s).

[0312] The term "negative regulator," as used herein, refers to a microglial gene that negatively regulates (e.g., reduces or inhibits) the expression and / or activity of another microglial gene or set of genes (e.g., a dysregulated microglial gene or a dysregulated microglial gene pathway).

[0313] The term "positive regulator," as used herein, refers to a microglial gene that positively regulates (e.g., increases or saturates) the expression and / or activity of another microglial gene or set of microglial genes (e.g., a dysregulated microglial gene or a dysregulated microglial gene pathway).

[0314] As used herein, the term "phosphate moiety" refers to a terminal phosphate group, including phosphate and modified phosphate. The phosphate moiety may be located at either terminus, but is preferred at the 5'-terminal nucleoside. In one aspect, the terminal phosphate is unmodified having the formula -OP(=O)(OH)OH. In another aspect, the terminal phosphate is modified such that one or more of the O and OH groups are replaced with H, O, S, N(R'), or an alkyl, amino protecting group, or unsubstituted or substituted alkyl where R' is H. In some embodiments, the 5' and or 3' terminal groups can each independently comprise 1-3 phosphate moieties that are unmodified (diphosphate or triphosphate) or modified.

[0315] In the context of the present invention, the term "oligonucleotide" refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or mimetics thereof. This term includes oligonucleotides composed of naturally occurring nucleobases, sugars and covalent internucleoside (backbone) linkages, as well as oligonucleotides having non-naturally occurring portions which function similarly. Such modified or substituted oligonucleotides are often preferred over natural forms due to desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for nucleic acid targets, and increased stability in the presence of nucleases.

[0316] As used herein, the term "reference subject" refers to a healthy control subject of the same or similar, e.g., age, sex, geographic region, and / or education level, as the subject treated with the composition of the present disclosure. A healthy reference subject is a subject that does not suffer from a disease associated with dysregulated expression of microglial genes or dysregulated expression of microglial gene pathways. Furthermore, a healthy reference subject is a subject that does not suffer from a disease associated with altered (e.g., increased or decreased) expression and / or activity of microglial genes.

[0317] As used herein, the terms "treat", "treated" or "treating" refer to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to prevent or slow (alleviate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical outcome. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms; reduction in the extent of the condition, disorder, or disease; a stabilized (i.e., non-worsening) state of the condition, disorder, or disease; a delay in the onset or progression of the condition, disorder, or disease; an improvement or remission (whether partial or total) of the condition, disorder, or disease, whether detectable or undetectable; an improvement in at least one measurable physical parameter, not necessarily discernible by the patient; or an enhancement or amelioration of the condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. "Treatment" also includes prolonging survival compared to the expected survival if not receiving treatment.

[0318] Genes Described Herein As used herein, the term "ABCA7" refers to the gene encoding the phospholipid-transporting ATPase ABCA7. The terms "ABCA7" and "phospholipid-transporting ATPase ABCA7" include wild-type forms of the ABCA7 gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type ABCA7. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type ABCA7 nucleic acid sequence (e.g., SEQ ID NO: 1, European Nucleotide Archive (ENA) Accession No. AF250238). SEQ ID NO: 1 is the wild-type gene sequence encoding the ABCA7 protein and is shown below. ATGGCCTTCTGGACACAGCTGATGCTGCTGCTCTGGAAGAATTTCATGTATCGCCGGAGA CAGCCGTCCAGCTCCTGGTCGAATTGCTGTGGCCTCTCTTCCTCTTCTTCATCCTGGTG GCTGTTCGCCACTCCCACCCGCCCCTGGAGCACCATGAATGCCACTTCCCAAACAAGCCA CTGCCATCGGCGGGCACCGTGCCCTGGCTCCAGGGTCTCATCTGTAATGTGAACAACACC TGCTTTCCGCAGCTGACACCGGGCGAGGAGCCCGGGCGCCTGAGCAACTTCAACGACTCC CTGGTCTCCCGGCTGCTAGCCGATGCCCGCACTGTGCTGGGAGGGGCCAGTGCCCACAGG ACGCTGGCTGGCCTAGGGAAGCTGATCGCCACGCTGAGGGCTGCACGCAGCACGGCCCAG CCTCAACCAACCAAGCAGTCTCCACTGGAACCACCCATGCTGGATGTCGCGGAGCTGCTG ACGTCACTGCTGCGCACGGAATCCCTGGGGTTGGCACTGGGCCAAGCCCAGGAGCCCTTG CACAGCTTGTTGGAGGCCGCTGAGGACCTGGCCCAGGAGCTCCTGGCGCTGCGCAGCCTG GTGGAGCTTCGGGCACTGCTGCAGAGACCCCGAGGGACCAGCGGCCCCCTGGAGTTGCTG TCAGAGGCCCTCTGCAGTGTCAGGGGACCTAGCAGCACAGTGGGCCCCTCCCTCAACTGG TACGAGGCTAGTGACCTGATGGAGCTGGTGGGGCAGGAGCCAGAATCCGCCCTGCCAGAC AGCAGCCTGAGCCCCGCCTGCTCGGAGCTGATTGGAGCCCTGGACAGCCACCCGCTGTCC CGCCTGCTCTGGAGACGCCTGAAGCCTCTGATCCTCGGGAAGCTACTCTTTGCACCAGAT ACACCTTTTACCCGGAAGCTCATGGCCCAGGTCAACCGGACCTTCGAGGAGCTCACCCTG CTGAGGGATGTCCGGGAGGTGTGGGAGATGCTGGGACCCCGGATCTTCACCTTCATGAAC GACAGTTCCAATGTGGCCATGCTGCAGCGGCTCCTGCAGATGCAGGATGAAGGAAGAAGG CAGCCCAGACCTGGAGGCCGGGACCACATGGAGGCCCTGCGATCCTTTCTGGACCCTGGG AGCGGTGGCTACAGCTGGCAGGACGCACACGCTGATGTGGGGCACCTGGTGGGCACGCTG GGCCGAGTGACGGAGTGCCTGTCCTTGGACAAGCTGGAGGCGGCACCCTCAGAGGCAGCC CTGGTGTCGCGGGCCCTGCAACTGCTCGCGGAACATCGATTCTGGGCCGGCGTCGTCTTC TTGGGACCTGAGGACTCTTCAGACCCCACAGAGCACCCAACCCCAGACCTGGGCCCCGGC CACGTGCGCATCAAAATCCGCATGGACATTGACGTGGTCACGAGGACCAATAAGATCAGG GACAGGTTTTGGGACCCTGGCCCAGCCGCGGACCCCCTGACCGACCTGCGCTACGTGTGG GGCGGCTTCGTGTACCTGCAAGACCTGGTGGAGCGTGCAGCCGTCCGCGTGCTCAGCGGC GCCAACCCCCGGGCCGGCCTCTACCTGCAGCAGATGCCCTATCCGTGCTATGTGGACGAC GTGTTCCTGCGTGTGCTGAGCCGGTCGCTGCCGCTCTTCCTGACGCTGGCCTGGATCTAC TCCGTGACACTGACAGTGAAGGCCGTGGTGCGGGAGAAGGAGACGCGGCTGCGGGACACC ATGCGCGCCATGGGGCTCAGCCGCGCGGTGCTCTGGCTAGGCTGGTTCCTCAGCTGCCTC GGGCCCTTCCTGCTCAGCGCCGCACTGCTGGTTCTGGTGCTCAAGCTGGGAGACATCCTC CCCTACAGCCACCCGGGCGTGGTCTTCCTGTTCTTGGCAGCCTTCGCGGTGGCCACGGTG ACCCAGAGCTTCCTGCTCAGCGCCTTCTTCTCCCGCGCCAACCTGGCTGCGGCCTGCGGC GGCCTGGCCTACTTCTCCCTCTACCTGCCCTACGTGCTGTGTGTGGCTTGGCGGGACCGG CTGCCCGCGGGTGGCCGCGTGGCCGCGAGCCTGCTGTCGCCCGTGGCCTTCGGCTTCGGC TGCGAGAGCCTGGCTCTGCTGGAGGAGCAGGGCGAGGGCGCGCAGTGGCACAACGTGGGC ACCCGGCCTACGGCAGACGTCTTCAGCCTGGCCCAGGTCTCTGGCCTTCTGCTGCTGGAC GCGGCGCTCTACGGCCTCGCCACCTGGTACCTGGAAGCTGTGTGCCCAGGCCAGTACGGG ATCCCTGAACCATGGAATTTTCCTTTTCGGAGGAGCTACTGGTGCGGACCTCGGCCCCCC AAGAGTCCAGCCCCTTGCCCCACCCCGCTGGACCCAAAGGTGCTGGTAGAAGAGGCACCG CCCGGCCTGAGTCCTGGCGTCTCCGTTCGCAGCCTGGAGAAGCGCTTTCCTGGAAGCCCG CAGCCAGCCCTGCGGGGGCTCAGCCTGGACTTCTACCAGGGCCACATCACCGCCTTCCTG GGCCACAACGGGGCCGGCAAGACCACCACCCTGTCCATCTTGAGTGGCCTCTTCCCACCC AGTGGTGGCTCTGCCTTCATCCTGGGCCACGACGTCCGCTCCAGCATGGCCGCCATCCGG CCCCACCTGGGCGTCTGTCCTCAGTACAACGTGCTGTTTGACATGCTGACCGTGGACGAG CACGTCTGGTTCTATGGGCGGCTGAAGGGTCTGAGTGCCGCTGTAGTGGGCCCCGAGCAG GACCGTCTGCTGCAGGATGTGGGGCTGGTCTCCAAGCAGAGTGTGCAGACTCGCCACCTC TCTGGTGGGATGCAACGGAAGCTGTCCGTGGCCATTGCCTTTGTGGGCGGCTCCCAAGTT GTTATCCTGGACGAGCCTACGGCTGGCGTGGATCCTGCTTCCCGCCGCGGTATTTGGGAG CTGCTGCTCAAATACCGAGAAGGTCGCACGCTGATCCTCTCCACCCACCACCTGGATGAG GCAGAGCTGCTGGGAGACCGTGTGGCTGTGGTGGCAGGTGGCCGCTTGTGCTGCTGTGGC TCCCCACTCTTCCTGCGCCGTCACCTGGGCTCCGGCTACTACCTGACGCTGGTGAAGGCC CGCCTGCCCCTGACCACCAATGAGAAGGCTGACACTGACATGGAGGGCAGTGTGGACACC AGGCAGGAAAAGAAGAATGGCAGCCAGGGCAGCAGAGTCGGCACTCCTCAGCTGCTGGCC CTGGTACAGCACTGGGTGCCCGGGGCACGGCTGGTGGAGGAGCTGCCACACGAGCTGGTG CTGGTGCTGCCCTACACGGGTGCCCATGACGGCAGCTTCGCCACACTCTTCCGAGAGCTA GACACGCGGCTGGCGGAGCTGAGGCTCACTGGCTACGGGATCTCCGACACCAGCCTCGAG GAGATCTTCCTGAAGGTGGTGGAGGAGTGTGCTGCGGACACAGATATGGAGGATGGCAGC TGCGGGCAGCACCTATGCACAGGCATTGCTGGCCTAGACGTAACCCTGCGGCTCAAGATG CCGCCACAGGAGACAGCGCTGGAGAACGGGGAACCAGCTGGGTCAGCCCCAGAGACTGAC CAGGGCTCTGGGCCAGACGCCGTGGGCCGGGTACAGGGCTGGGCACTGACCCGCCAGCAG CTCCAGGCCCTGCTTCTCAAGCGCTTTCTGCTTGCCCGCCGCAGCCGCCGCGGCCTGTTC GCCCAGATCGTGCTGCCTGCCCTCTTTGTGGGCCTGGCCCTCGTGTTCAGCCTCATCGTG CCTCCTTTCGGGCACTACCCGGCTCTGCGGCTCAGTCCCACCATGTACGGTGCTCAGGTG TCCTTCTTCAGTGAGGACGCCCCAGGGGACCCTGGACGTGCCCGGCTGCTCGAGGCGCTG CTGCAGGAGGCAGGACTGGAGGAGCCCCCAGTGCAGCATAGCTCCCACAGGTTCTCGGCA CCAGAAGTTCCTGCTGAAGTGGCCAAGGTCTTGGCCAGTGGCAACTGGACCCCAGAGTCT CCATCCCCAGCCTGCCAGTGTAGCCAGCCCGGTGCCCGGCGCCTGCTGCCCGACTGCCCG GCTGCAGCTGGTGGTCCCCCTCCGCCCCAGGCAGTGACCGGCTCTGGGGAAGTGGTTCAG AACCTGACAGGCCGGAACCTGTCTGACTTCCTGGTCAAGACCTACCCGCGCCTGGTGCGC CAGGGCCTGAAGACTAAGAAGTGGGTGAATGAGGTCAGGTACGGAGGCTTCTCGCTGGGG GGCCGAGACCCAGGCCTGCCCTCGGGCCAAGAGTTGGGCCGCTCAGTGGAGGAGTTGTGG GCGCTGCTGAGTCCCCTGCCTGGCGGGGCCCTCGACCGTGTCCTGAAAAACCTCACAGCC TGGGCTCACAGCCTGGACGCTCAGGACAGTCTCAAGATCTGGTTCAACAACAAAGGCTGG CACTCCATGGTGGCCTTTGTCAACCGAGCCAGCAACGCAATCCTCCGTGCTCACCTGCCC CCAGGCCGGGCCCGCCACGCCCACAGCATCACCACACTCAACCACCCCTTGAACCTCACCC AAGGAGCAGCTGTTTGAGGCTGCATTGATGGCCTCCTCGGTGGACGTCCTCGTCTCCATC TGTGTGGTCTTGCCATGTCCTTTGTCCCGGCCAGCTTCACTCTTGTCCTCATTGAGGAG CGAGTCACCCGAGCCAAGCACCTGCAGCTCATGGGGGGCCTGTCCCCCACCCCTCTACTGG CTTGGCAACTTTCTCTGGGACATGTGTAACTACTTGGTGCCAGCATGCATCGTGGTGCTC ATCTTTCTGGCCTTCCAGCAGAGGGCATATGTGGCCCCTGCCAACCTGCCTGCTCTCCTG CTGTTGCTACTACTGTATGGCTGGTCGATCACACCGCTCATGTACCCAGCCTCCTTCTTC TTCTCCGTGCCCAGCACAGCCTATGTGGTGCTCACCTGCATAAACCTCTTTATTGGCATC AATGGAAGCATGGCCACCTTTGTGCTTGAGCTCTTCTCTGATCAGAAGCTGCAGGAGGTG AGCCGGATCTTGAAACAGGTCTTCCTTATCTTCCCCCACTTCTGCTTGGGCCGGGGGCTT ATTGACATGGTGCGGAACCAGGCCATGGCTGATGCCTTTGAGCGCTTGGGAGACAGGCAG TTCCAGTCACCCCTGCGCTGGGAGGTGGTCGGCAAGAACCTCTTGGCCATGGTGATACAG GGGCCCCTCTTCCTTCTCTTCACACTACTGCTGCAGCACCGAAGCCAACTCCTGCCACAG CCCAGGGTGAGGTCTCTGCCACTCCTGGGAGAGGAGGACGAGGATGTAGCCCGTGAACGG GAGCGGGTGGTCCAAGGAGCCACCCAGGGGGATGTGTTGGTGCTGAGGAACTTGACCAAG GTATACCGTGGGCAGAGGATGCCAGCTGTTGACCGCTTGTGCCTGGGGATTCCCCCTGGT GAGTGTTTTGGGCTGCTGGGTGTGAATGGAGCAGGGAAGACGTCCACGTTTCGCATGGTG ACGGGGGACACATTGGCCAGCAGGGGCGAGGCTGTGCTGGCAGGCCACAGCGTGGCCCGG GAACCCAGTGCTGCGCACCTCAGCATGGGATACTGCCCTCAATCCGATGCCATCTTTGAG CTGCTGACGGGCCGCGAGCACCTGGAGCTGCTTGCGCGCCTGCGCGGTGTCCCGGAGGCC CAGGTTGCCCAGACCGCTGGCTCGGGCCTGGCGCGTCTGGGACTCTCATGGTACGCAGAC CGGCCTGCAGGCACCTACAGCGGAGGGAACAAACGCAAGCTGGCGACGGCCCTGGCGCTG GTTGGGGACCCAGCCGTGGTGTTTCTGGACGAGCCGACCACAGGCATGGACCCCAGCGCG CGGCGCTTCCTTTGGAACAGCCTTTTGGCCGTGGTGCGGGAGGGCCGTTCAGTGATGCTC ACCTCCCATAGCATGGAGGAGTGTGAAGCGCTCTGCTCGCGCCTAGCCATCATGGTGAAT GGGCGGTTCCGCTGCCTGGGCAGCCCGCAACATCTCAAGGGCAGATTCGCGGCGGGTCAC ACACTGACCCTGCGGGTGCCCGCCGCAAGGTCCCAGCCGGCAGCGGCCTTCGTGGCGGCC GAGTTCCCTGGGTCGGAGCTGCGCGAGGCACATGGAGGCGCCTGCGCTTCCAGCTGCCG CCGGGAGGGCGCTGGCCCCTGGCGCGCGTCTTTGGAGAGCTGGCGGTCACGGCGCAGAG CACGGCGTGGAGGACTTTTCCGTGAGCCAGACGATGCTGGAGGAGGTATTCTTGTACTTC TCCAAGGACCAGGGGAAGGACGAGGACACCGAAGAGCAGAAGGAGGCAGGAGTGGGAGTG GACCCCGCGCCAGGCCTGCAGCACCCCAAACGCGTCAGCCAGTTCCTCGATGACCCTAGC ACTGCCGAGACTGTGCTCTGAGCCTCCCTCCCCTGCGGGGCCGCGGGGAGGCCCTGGGAA TGGCAAGGGCAAGGTAGAGTGCCTAGGAGCCCTGGACTCAGGCTGGCAGAGGGGCTGGTG CCCTGGAGAAAATAAAGAGAAGGCTGGAGAGAAGCCGTGCTTGGTGAA (query number 1)

[0319] As used herein, the term "ABI3" refers to the gene encoding ABI gene family member 3. The terms "ABI3" and "ABI gene family member 3" include wild-type forms of the ABI3 gene, as well as variants of the wild-type ABI3 (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type ABI3 nucleic acid sequence (e.g., SEQ ID NO: 2, ENA Accession No. AF037886). SEQ ID NO: 2 is the wild-type gene sequence encoding the ABI3 protein and is shown below. TCCTATCCACCCTCCACTCCCCTGTCCCTTGGTGACTCATCCCTGAGCTTCCCAAGGAAG CCCCCACCCTCTGCCCTTTCCTCCCGCCTTCCATGAGTGGAAAATCCACCTCCGCCCCCT ATAGCAGGCCAGCCCCCTTCCTCCCCAGTCTCCGACCCCATCCCCCAGCCGACCAGTTTC CTCTCCAGGACCAGGGAGCAATCACAGCTGCCCCGACCTTGGCTTCCTCTGCTGGGTGGG ATTGGGGGCTGGGCCCCCAAATGGGCCCCTGGCTTCCCCCTTCCTCTGGGCAGGGGACAG AGAGACACAGGCTCGGGGAGCAGGACTGACTTCCTCTTGTCCCGGAATGAGCATGCCTGC CCTTTGCAAGCAGGTTTGGGTCTCACGCAGAGGAAACCAAAAGCAATAAGAGGGAGGGAA GGCAGAGCAACCAATCAAGGGCAGGGTGAGACTCAAAAACGAGCGGGCTCCCTGGGGAGCC AGACAGAGGCTGGGGGTGATGGCGGAGCTACAGCAGCTGCAGGAGTTTGAGATCCCCACT GGCCGGGAGGCTCTGAGGGGCAACCACAGTGCCCTGCTGCGGGTCGCTGACTACTGCGAG GACAACTATGTGCAGGCCACAGACAAGCGGAAGGCGCTGGAGGAGACCATGGCCTTCACT ACCCAGGCACTGGCCAGCGTGGCCTACCAGGTGGGCAACCTGGCCGGGCACACTCTGCGC ATGTTGGACCTGCAGGGGGCCGCCCTGCGGCAGGTGGAAGCCCGTGTAAGCACGCTGGGC CAGATGGTGAACATGCATATGGAGAAGGTGGCCCGAAGGGAGATCGGCACCTTAGCCACT GTCCAGCGGCTGCCCCCCGGCCAGAAGGTCATCGCCCCAGAGAACCTACCCCCTCTCACG CCCTACTGCAGGAGACCCCTCAACTTTGGCTGCCTGGACGACATTGGCCATGGGATCAAG GACCTCAGCACGCAGCTGTCAAGAACAGGCACCCTGTCTCGAAAGAGCATCAAGGCCCCT GCCACACCCGCCTCCGCCACCTTGGGGAGACCACCCCGGATTCCCGAGCCAGTGCACCTG CCGGTGGTGCCCGACGGCAGACTCTCCGCCGCCTCCTCTGCGTCTTCCCTGGCCTCGGCC GGCAGCGCCGAAGGTGTCGGTGGGGCCCCCACGCCCAAGGGGCAGGCAGCACCTCCAGCC CCACCTCTCCCCAGCTCCTTGGACCCACCTCCTCCACCAGCAGCCGTCGAGGTGTTCCAG CGGCCTCCCACGCTGGAGGAGTTGTCCCCACCCCCACCGGACGAAGAGCTGCCCCTGCCA CTGGACCTGCCTCCTCCTCCACCCCTGGATGGAGATGAATTGGGGCTGCCTCCACCCCCA CCAGGATTTGGGCCTGATGAGCCCAGCTGGGTGCCTGCCTCATACTTGGAGAAAGTGGTG ACACTGTACCCATACACCAGCCAGAAGGACAATGAGCTCTCCTTCTCTGAGGGCACTGTC ATCTGTGTCACTCGCCGCTACTCCGATGGCTGGTGCGAGGGCGTCAGCTCAGAGGGGACT GGATTCTTCCCTGGGAACTATGTGGAGCCCAGCTGCTGACAGCCCAGGGCTCTCTGGGCA GCTGATGTCTGCACTGAGTGGGTTTCATGAGCCCCAAGCCAAAACCAGCTCCAGTCACAG CTGGACTGGGTCTGCCCACCTCTTGGGCTGTGAGCTGTGTTCTGTCCTTCCTCCCATCGG AGGGAGAAGGGGTCCTGGGGAGAGAGAATTTATCCAGAGGCCTGCTGCAGATGGGGAAGA GCTGGAAACCAAGAAGTTTGTCAACAGAGGACCCCTACTCCATGCAGGACAGGGTCTCCT GCTGCAAGTCCCAACTTTGAATAAAACAGATGATGTCCTGTGACTGCCCCACAGAGATAA GGGGCCAGGAGGGATTGAAAGGCATCCCAGTTCTAAGGCTGCTGCTAATTACAGCCCCCA ACCTCCAACCCACCAGCTGACCTAGAAGCAGCATCTTCCCATTTCCTCAGTACCCACAAA GTGCAGCCACATTGGACCCCAGACACCCCTCTGCAGCCATTGACTGCAACTTGTTCTTT TGCCCATTAAAAAAAAAAAAAAAAAAAAA (SEQ ID NO:2)

[0320] As used herein, the term "ADAM10" refers to the gene encoding ADAM metallopeptidase domain 10. The terms "ADAM10" and "ADAM metallopeptidase domain 10" include wild-type forms of the ADAM10 gene, as well as variants of the wild-type ADAM10 (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type ADAM10 nucleic acid sequence (e.g., SEQ ID NO: 3, NCBI Reference Sequence: NM_001110.3). SEQ ID NO: 3 is the wild-type gene sequence encoding the ADAM10 protein and is shown below. (SEQ ID NO:3)

[0321] The terms "APOC1" and "apolipoprotein C1" include wild-type forms of the APOC1 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type APOC1. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type APOC1 nucleic acid sequence (e.g., SEQ ID NO: 4, NCBI Reference Sequence: NM_001645). SEQ ID NO: 4 is the wild-type gene sequence encoding the APOC1 protein and is shown below. AACGCTCACGGGACAGGGGCAGAGGAGAAAAACGTGGGTGGACAGAGGGAGGCAGGCGGTCAGGGGAAGGCTCAGGAGGAGGGAGATCAACATCAACCTGCCCCGCCCCCTCCCCAGCCTGATAAAGGTCCTGCGGGCAGGACAGGACCTCCCAACCAAGCCCTCCAGCAAGGATTCAGAGTGCCCCTCCGGCCTCGCCATGAGGCTCTTCCTGTCGCTCCCGGTCCTGGTGGTGGTTCTGTCGATCGTCTTGGAAGGCCCAGCCCCAGCCCAGGGGACCCCAGACGTCTCCAGTGCCTTGGATAAGCTGAAGGAGTTTGGAAACACACTGGAGGACAAGGCTCGGGAACTCATCAGCCGCATCAAACAGAGTGAACTTTCTGCCAAGATGCGGGAGTGGTTTTCAGAGACATTTCAGAAAGTGAAGGAGAAACTCAAGATTGACTCATGAGGACCTGAAGGGTGACATCCCAGGAGGGGCCTCTGAAATTTCCCACACCCCAGCGCCTGTGCTGAGGACTCCCTCCATGTGGCCCCAGGTGCCACCAATAAAAATCCTACAGAAAATTCAAAAAAAAAAAAAAAAAA (SEQ ID NO: 4)

[0322] As used herein, the term "APOE" refers to the gene encoding apolipoprotein E. The terms "APOE" and "apolipoprotein E" include wild-type forms of the APOE gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type APOE. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type APOE nucleic acid sequence (e.g., SEQ ID NO: 5, ENA Accession No. M12529). SEQ ID NO:5 is the wild-type gene sequence encoding the APOE protein and is shown below. CCCCAGCGGAGGTGAAGGACGTCCTTCCCCAGGAGCCGACTGGCCAATCACAGGCAGGAA GATGAAGGTTCTGTGGGCTGCGTTGCTGGTCACATTCCTGGCAGGATGCCAGGCCAAGGT GGAGCAAGCGGTGGAGACAGAGCCGGAGCCCGAGCTGCGCCAGCAGACCGAGTGGCAGAG CGGCCAGCGCTGGGAACTGGCACTGGGTCGCTTTTGGGATTACCTGCGCTGGGTGCAGAC ACTGTCTGAGCAGGTGCAGGAGGAGCTGCTCAGCTCCCAAGTCACCCAAGAACTGAGGGC GCTGATGGACGAGACCATGAAGGAGTTGAAGGCCTACAAATCGGAACTGGAGGAACAACT GACCCCGGTAGCGGAGGAGACGCGGGCACGGCTGTCCAAGGAGCTGCAGACGGCGCAGGC CCGGCTGGGCGCGGACATGGAGGACGTGTGCGGCCGCCTGGTGCAGTACCGCGGCGAGGT GCAGGCCATGCTCGGCCAGAGCACCGAGGAGCTGCGGGTGCCCTCCGCCTCCCACCTGCG CAAGCTGCGTAAGCGGCTCCTCCGCGATCCCGATGACCTGCAGAAGCGCCTGGCAGTGTA CCAGGCCGGGGCCCGCGAGGGCGCCGAGCGCGGCCTCACGCGCCATCCGCGAGCGCCTGGG GCCCCTGGTGGAACAGGGCCGCGTGCGGGCCGCCACTGTGGGCTCCCTGGCCGGCCAGCC GCTACAGGAGCGGGGCCCAGGCCTGGGGCGAGCGGCTGCGCGCGCGGATGGAGGAGATGGG CAGTCGGACCCGCGACCGCCTGGACGAGGTGAAGGAGCAGGTGGCGGAGGTGCCGGCCAA GCTGGAGGAGCAGGCCCAGCAGATACGCCTGCAGGCCGAGGCCTTCCAGGCCCGCCTCAA GAGCTGGTTCGAGCCCCTGGTGGAAGACATGCAGCGCCAGTGGGCCGGGCTGGTGGAGAA GGTGCAGGCTGCCGTGGGCACCAGCGCCGCCCCTGTGCCAGCGACAATCACTGAACGCC GAAGCCTGCAGCCATGCGACCCCACGCCACCCCGTGCCTCCTGCCTCCGCGCAGCCTGCA GCGGGAGACCCTGTCCCCGCCCCAGCCGTCCTCCTGGGGTGGACCCTAGTTTAATAAAGA TTCACCAAGTTTCACGC (query number 5)

[0323] As used herein, the term "AXL" refers to a gene encoding the tyrosine protein kinase receptor UFO. The terms "AXL" and "tyrosine protein kinase receptor UFO" include wild-type forms of the AXL gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type AXL. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type AXL nucleic acid sequence (e.g., SEQ ID NO: 6, ENA Accession No. M76125). SEQ ID NO:6 is the wild-type gene sequence encoding the AXL protein and is shown below. GCTGGGCAAAGCCGGTGGCAAGGGCCTCCCCTGCCGCTGTGCCAGGCAGGCAGTGCCAAA TCCGGGGAGCCTGGAGCTGGGGGGAGGGCCGGGGACAGCCCGGCCCTGCCCCCTCCCCCG CTGGGAGCCCAGCAACTTCTGAGGAAAGTTTGGCACCCATGGCGTGGCGGTGCCCCAGGA TGGGCAGGGTCCCGCTGGCCTGGTGCTTGGCGCTGTGCGGCTGGGCGTGCATGGCCCCCA GGGGCACGCAGGCTGAAGAAAGTCCCTTCGTGGCAACCCAGGGAATATCACAGGTGCCC GGGGACTCACGGGCACCCTTCGGTGTCAGCTCCAGGTTCAGGGAGAGCCCCCCGAGGTAC ATTGGCTTCGGGATGGACAGATCCTGGAGCTCGCGGACAGCACCCAGACCCAGGTGCCCC TGGGTGAGGATGAACAGGATGACTGGATAGTGGTCAGCCAGCTCAGAATCACCTCCCTGC AGCTTTCCGACACGGGACAGTACCAGTGTTTGGTGTTTCTGGGACATCAGACCTTCGTGT CCCAGCCTGGCTATGTTGGGCTGGAGGGCTTGCCTTACTTCCTGGAGGAGCCCGAAGACA GGACTGTGGCCGCCAACACCCCCTTCAACCTGAGCTGCCAAGCTCAGGGACCCCCAGAGC CCGTGGACCTACTCTGGCTCCAGGATGCTGTCCCCCTGGCCACGGCTCCAGGTCACGGCC CCCAGCGCAGCCTGCATGTTCCAGGGCTGAACAAGACATCCTCTTTCTCCTGCGAAGCCC ATAACGCCAAGGGGGTCACCACATCCCGCACAGCCACCATCACAGTGCTCCCCCAGCAGC CCCGTAACCTCCACCTGGTCTCCCGCCAACCCACGGAGCTGGAGGTGGCTTGGACTCCAG GCCTGAGCGGCATCTACCCCCTGACCCACTGCACCCTGCAGGCTGTGCTGTCAGACGATG GGATGGGCATCCAGGCGGGAGAACCAGACCCCCCAGAGGAGCCCCTCACCTCGCAAGCAT CCGTGCCCCCCCATCAGCTTCGGCTAGGCAGCCTCCATCCTCACACCCCTTATCACATCC GCGTGGCATGCACCAGCAGCCAGGGCCCCTCATCCTGGACCCACTGGCTTCCTGTGGAGA CGCCGGAGGGAGTGCCCCTGGGCCCCCCTAAGAACATTAGTGCTACGCGGAATGGGAGCC AGGCCTTCGTGCATTGGCAAGAGCCCCGGGCGCCCCTGCAGGGTACCCTGTTAGGGTACC GGCTGGCGTATCAAGGCCAGGACACCCCAGAGGTGCTAATGGACATAGGGCTAAGGCAAG AGGTGACCCTGGAGCTGCAGGGGGACGGGTCTGTGTCCAATCTGACAGTGTGTGTGGCAG CCTACACTGCTGCTGGGGATGGACCCTGGAGCCTCCCAGTACCCCTGGAGGCCTGGCGCC CAGTGAAGGAACCTTCAACTCCTGCCTTCTCGTGGCCCTGGTGGTATGTACTGCTAGGAG CAGTCGTGGCCGCTGCCTGTGTCCTCATCTTGGCTCTCTTCCTTGTCCACCGGCGAAAGA AGGAGACCCGTTATGGAGAAGTGTTTGACCAACAGTGGAAAGAGGTGAACTGGTAGTCA GGTACCGCGTGCGCAAGTCCTACAGTCGTCGGACCACTGAAGCTACCTTGAACAGCCTGG GCATCAGTGAAGAGCTGAAGGAGAAGCTGCGGGATGTGATGGTGGACCGGCACAAGGTGG CCCTGGGAAGACTCTGGGAGAGGGAGAGTTTGGAGCTGTGATGGAAGGCCAGCTCCAACC AGGACGACTCCATCCTCAAGGTGGCTGTGAAGACGATGAAGATTGCCATCTGCACGAGGT CAGAGCTGGAGGATTTCCTGAGTGAAGCGGTCTGCATGAAGGAATTTGACCATCCCAACG TCATGAGGCTCATCGGTGTCTGTTTCCAGGGTTCTGAACGAGAGAGCTTCCCAGCACCTG TGGTCATCTTACCTTTCATGAAACATGGAGACCTACACAGCTTCCTCCTCTATTCCCGGC TCGGGGACCAGCCAGTGTACCTGCCCACTCAGATGCTAGTGAAGTTCATGGCAGACATCG CCAGTGGCATGGAGTATCTGAGTACCAAGAGATTCATACACCGGGACCTGGCGGCCAGGA ACTGCATGCTGAATGAGAACATGTCCGTGTGTGTGGCGGACTTCGGGCTCTCCAAGAAGA TCTACAATGGGGACTACTACCGCCAGGGACGTATCGCCAAGATGCCAGTCAAGTGGATTG CCATTGAGAGTCTAGCTGACCGTGTCTACACCAGCAAGAGCGATGTGTGGTCCTTCGGGG TGACAATGTGGGAGATTGCCACAAGAGGCCAAACCCCATATCCGGGCGTGGAGAACAGCG AGATTTATGACTATCTGCGCCAGGGAAATCGCCTGAAGCAGCCTGCGGACTGTCTGGATG GACTGTATGCCTTGATGTCGCGGTGCTGGGAGCTAAATCCCCAGGACCGGCCAAGTTTTA CAGAGCTGCGGGAAGATTTGGAGAACACACTGAAGGCCTTGCCTCCTGCCCAGGAGCCTG ACGAAATCCTCTATGTCAACATGGATGAGGGTGGAGGTTATCCTGAACCCCCTGGAGCTG CAGGAGGAGCTGACCCCCCAACCCAGCCAGACCCTAAGGATTCCTGTAGCTGCCTCACTG CGGCTGAGGTCCATCCTGCTGGACGCTATGTCCTCTGCCCTTCCACAACCCCTAGCCCCG CTCAGCCTGCTGATAGGGGCTCCCCAGCAGCCCCAGGGCAGGAGGATGGTGCCTGAGACA ACCCTCCACCTGGTACTCCCTCTCAGGATCCAAGCTAAGCACTGCCACTGGGGAAAACTC CACCTTCCCACTTTTCCACCCCACGCCTTATCCCCACTTGCAGCCCTGTCTTCCTACCTA TCCCACCTCCATCCCAGACAGGTCCCTCCCCTTCTCTGTGCAGTAGCATCACCTTGAAAG CAGTAGCATCACCATCTGTAAAAGGAAGGGGTTGGATTGCAATATCTGAAGCCCTCCCAG GTGTTAACATTCCAAGACTCTAGAGTCCAAGGTTTAAAGAGTCTAGATTCAAAGGTTCTA GGTTTCAAAGATGCTGTGAGTCTTTGGTTCTAAGGACCTGAAATTCCAAAGTCTCTAATT CTATTAAAGTGCTAAGGTTCTAAGGCAAAAAAAAAAAAAAAAAAAAA (SEQ ID NO:6)

[0324] As used herein, the term "BIN1" refers to the gene encoding Myc box-dependent interacting protein 1. The terms "BIN1" and "Myc box-dependent interacting protein 1" include wild-type forms of the BIN1 gene, as well as variants of the wild-type BIN1 (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type BIN1 nucleic acid sequence (e.g., SEQ ID NO: 7, ENA Accession No. AF004015). SEQ ID NO: 7 is the wild-type gene sequence encoding the BIN1 protein and is shown below. ATGGCAGAGATGGGCAGTAAAGGGGTGACGGCGGGAAAGATCGCCAGCAACGTGCAGAAG AAGCTCACCCGCGCGCAGGAGAAGGTTCTCCAGAAGCTGGGGAAGGCAGATGAGACCAAG GATGAGCAGTTTGAGCAGTGCGTCCAGAATTTCAACAAGCAGCTGACGGAGGGCACCCGG CTGCAGAAGGATCTCCGGACCTACCTGGCCTCCGTCAAAGCCATGCACGAGGCTTCCAAG AAGCTGAATGAGTGTCTGCAGGAGGTGTATGAGCCCGATTGGCCCGGCAGGGATGAGGCA AACAAGATCGCAGAGAACAACGACCTGCTGTGGATGGATTACCACCAGAAGCTGGTGGAC CAGGCGCTGCTGACCATGGACACGTACCTGGGCCAGTTCCCCGACATCAAGTCACGCATT GCCAAGCGGGGGCGCAAGCTGGTGGACTACGACAGTGCCCGGCACCACTACGAGTCCCTT CAAACCGCCAAAAAGAAGGATGAAGCCAAAATTGCCAAGCCTGTCTCGCTGCTTGAGAAA GCCGCCCCCCAGTGGTGCCAAGGCAAACTGCAGGCTCATCTCGTAGCTCAAACTAACCTG CTCCGAAATCAGGCCGAGGAGGAGCTCATCAAAGCCCAGAAGGTGTTTGAGGAGATGAAT GTGGATCTGCAGGAGGAGCTGCCGTCCCTGTGGAACAGCCGCGTAGGTTTCTACGTCAAC ACGTTCCAGAGCATCGCGGGCCTGGAGGAAAACTTCCACAAGGAGATGAGCAAGCTCAAC CAGAACCTCAATGATGTGCTGGTCGGCCTGGAGAAGCAACACGGGAGCAACACCTTCACG GTCAAGGCCCAGCCCAGTGACAACGCGCCTGCAAAAGGGAACAAGAGCCCTTCGCCTCCA GATGGCTCCCCTGCCGCCACCCCCGAGATCAGAGTCAACCACGAGCCAGAGCCGGCCGGC GGGGCCACGCCCGGGGCCACCCTCCCCAAGTCCCCATCTCAGCTCCGGAAAGGCCCACCA GTCCCTCCGCCTCCCAAACACACCCCGTCCAAGGAAGTCAAGCAGGAGCAGATCCTCAGC CTGTTTGAGGACACGTTTGTCCCTGAGATCAGCGTGACCACCCCCTCCCAGTTTGAGGCC CCGGGGCCTTTCTCGGAGCAGGCCAGTCTGCTGGACCTGGACTTTGACCCCCTCCCGCCC GTGACGAGCCCTGTGAAGGCACCCACGCCCTCTGGTCAGTCAATTCCATGGGACCTCTGG GAGCCCACAGAGAGTCCAGCCGGCAGCCTGCCTTCCGGGGAGCCCAGCGCTGCCGAGGGC ACCTTTGCTGTGTCCTGGCCCAGCCAGACGGCCGAGCCGGGGCCTGCCCAACCAGCAGAG GCCTCGGAGGTGGCGGGTGGGACCCAACCTGCGGCTGGAGCCCAGGAGCCAGGGGAGACG GCGGCAAGTGAAGCAGCCTCCAGCTCTCTTCCTGCTGTCGTGGTGGAGACCTTCCCAGCA ACTGTGAATGGCACCGTGGAGGGCGGCAGTGGGGCCGGGCGCTTGGACCTGCCCCCAGGT TTCATGTTCAAGGTACAGGCCCAGCACGACTACACGGCCACTGACACAGACGAGCTGCAG CTCAAGGCTGGTGATGTGGTGCTGGGTGATCCCCTTCCAGAACCCTGAAGAGCAGGATGAA GGCTGGCTCATGGGCGTGAAGGAGAGCGACTGGAACCAGCACAAGGAGCTGGAGAAGTGC CGTGGCGTCTTCCCCGAGAACTTCACTGAGAGGGTCCCATGA (SEQ ID NO:7)

[0325] As used herein, the term "C1QA" refers to the gene encoding the complement C1qA chain. The terms "C1QA" and "complement C1qA chain" include wild-type forms of the C1QA gene, as well as variants of the wild-type C1QA (e.g., splice variants and polymorphisms). An example of such a variant is a nucleic acid having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type C1QA nucleic acid sequence (e.g., SEQ ID NO: 8, NCBI Reference Sequence: NM_015991.3). SEQ ID NO: 8 is the wild-type gene sequence encoding the C1QA protein and is shown below. (SEQ ID NO:8)

[0326] As used herein, the term "C3" refers to a gene encoding complement C3. The terms "C3" and "complement C3" include wild-type forms of the C3 gene, as well as variants of wild-type C3 (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type C3 nucleic acid sequence (e.g., SEQ ID NO: 9, NCBI Reference Sequence: NM_000064.3). SEQ ID NO:9 is the wild-type gene sequence encoding the C3 protein and is shown below. GTTATATTCTCAAAAAAAAAAAAAAA (SEQ ID NO:9)

[0327] As used herein, the term "C9orf72" refers to a gene encoding guanine nucleotide exchange C9orf72. The terms "C9orf72" and "guanine nucleotide exchange C9orf72" include wild-type forms of the C9orf72 gene, as well as variants of wild-type C9orf72 (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type C9orf72 nucleic acid sequence (e.g., SEQ ID NO: 10, ENA Accession No. JN681271). SEQ ID NO: 10 is the wild-type gene sequence encoding the C9orf72 protein and is shown below. AGGAAAGAGAGGTGCGTCAAACAGCGACAAGTTCCGCCCACGTAAAAGATGACGCTTGGT GTGTCAGCCGTCCCTGCTGCCCGGTTGCTTCTCTTTTGGGGGCGGGGTCTAGCAAGAGCA GGTGTGGGTTTAGGAGATATCTCCGGAGCATTTGGATAATGTGACAGTTGGAATGCAGTG ATGTCGACTCTTTGCCCACCGCCATCTCCAGCTGTTGCCAAGACAGAGATTGCTTTAAGT GGCAAATCACCTTTATTAGCAGCTACTTTTGCTTACTGGGACAATATTCTTGGTCCTAGA GTAAGGCACATTTGGGCTCCAAAGACAGAACAGGTACTTCTCAGTGATGGAGAAATAACT TTTCTTGCCAACCACACTCTAAATGGAGAAATCCTTCGAAATGCAGAGAGTGGTGCTATA GATGTAAAGTTTTTTTGTCTTGTCTGAAAAGGGAGTGATTATTGTTTCATTAATCTTTGAT GGAAACTGGAATGGGGATCGCAGCACATATGGACTATCAATTATACTTCCACAGACAGAA CTTAGTTTCTACCTCCCACTTCATAGAGTGTGTGTTGATAGATTAACACATATAATCCGG AAAGGAAGAATATGGATGCATAAGGAAAGACAAGAAAATGTCCAGAAGATTATCTTAGAA GGCACAGAGAGAATGGAAGATCAGGGTCAGAGTATTATTCCAATGCTTACTGGAGAAGTG ATTCCTGTAATGGAACTGCTTTCATCTATGAAATCACACAGTGTTCCTGAAGAAAATAGAT ATAGCTGATACAGTACTCAATGATGATGATATTGGTGACAGCTGTCATGAAGGCTTTCTT CTCAATGCCATCAGCTCACACTTGCAAACCTGTGGCTGTTCCGTTGTAGTAGGTAGCAGT GCAGAGAAAGTAAATAAGATAGTCAGAACATTATGCCTTTTTCTGACTCCAGCAGAGAGA AAATGCTCCAGGTTATGTGAAGCAGAATCATCATTTAAATATGAGTCAGGGCTCTTTGTA CAAGGCCTGCTAAAGGATTCAACTGGAAGCTTTGTGCTGCCTTTCCGGCAAGTCATGTAT GCTCCATATCCCACCACACACATAGATGTGGATGTCAATACTGTGAAGCAGATGCCACCC TGTCATGAACATATTTATAATCAGCGTAGATACATGAGATCCGAGCTGACAGCCTTCTGG AGAGCCACTTCAGAAGAAGACATGGCTCAGGATACGATCATCTACACTGACGAAAGCTTT ACTCCTGATTTGAATATTTTTCAAGATGTCTTACACAGAGACACTCTAGTGAAAGCCTTC CTGGATCAGGTCTTTCAGCTGAAACCTGGCTTATCTCTCAGAAGTACTTTCCTTGCACAG TTTCTACTTGTCCTTCACAGAAAAGCCTTGACACTAATAAAATATATAGAAGACGATACG CAGAAGGGAAAAAAGCCCTTTAAATCTCTTCGGAACCTGAAGATAGACCTTGATTTAACA GCAGAGGGCGATCTTAACATAATAATGGCTCTGGCTGAGAAAATTAAACCAGGCCTACAC TCTTTTATCTTTGGAAGACCTTTCTACACTAGTGTGCAAGAACGAGATGTTCTAATGACT TTTAAATGTGTAACTTAATAAGCCTATTCCATCACAATCATGATCGCTGGTAAAGTAGC TCAGTGGTGTGGGGAAACGTTCCCCTGGATCATACTCCAGAATTCTGCTCTCAGCAATTG CAGTTAAGTAAGTTACACTACAGTTCTCACAAGAGCCTGTGAGGGGATGTCAGGTGCATC ATTACATTGGGTGTCTCTTTTCCTAGATTTATGCTTTTGGGATACAGACCTATGTTTACA ATATAATAAATATTATTGCTATCTTTTAAAGATATAATAATAGGATGTAAACTTGACCAC AACTACTGTTTTTTTGAAATACATGATTCATGGTTACATGTGTCAAGGTGAAATCTGAG TTGGCTTTTACAGATAGTTGACTTTCTATCTTTTGGCATTCTTTGGTGTGTAGAATTACT GTAATACTTCTGCAATCAACTGAAAACTAGAGCCTTTAAATGATTTCAATTCCACAGAAA GAAAGTGAGCTTGAACATAGGATGAGCTTTAGAAAGAAAATTGATCAAGCAGATGTTTAA TTGGAATTGATTATTAGATCCTACTTTGTGGATTTAGTCCCTGGGATTCAGTCTGTAGAA ATGTCTAATAGTTCTCTATAGTCCTTGTTCCTGGTGAACCACAGTTAGGGTGTTTTGTTT ATTTTATTGTTCTTGCTATTGTTGATATTCTATGTAGTTGAGCTCTGTAAAAGGAAATTG TATTTTATGTTTTAGTAATTGTTGCCAACTTTTTAAATTAATTTTCATTATTTTTGAGCC AAATTGAAATTGTGCACCTCCTGTGCCTTTTTTCTCCTTAGAAAATCTAATTACTTGGAAC AAGTTCAGATTTCACTGGTCAGTCATTTTCATCTTGTTTTCTCTTGCTAAGTCTTACCA TGTACCTGCTTTGGCAATCATTGCAACTCTGAGATTATAAAATGCCTTAGAGAATATACT AACTAATAAGATCTTTTTTTCAGAAACAGAAAATAGTTCCTTGAGTACTTCCTTCTTGCA TTTCTGCCTATGTTTTTGAAGTTGTTGCTGTTTGCCTGCAATAGGCTATAAGGAATAGCA GGAGAAATTTTACTGAAGTGCTGTTTTCCTAGGTGCTACTTTGGCAGAGCTAAGTTATCT TTTGTTTTCTTAATGCGTTTGGACCATTTTGCTGGCTATAAAATAACTGATTAATATAAT TCTAACACAATGTTGACATTGTAGTTACACAAACACAAATAAATATTTTATTTAAAATTC TGGAAGTAATATAAAAGGGAAAATATATTTATAAGAAAGGGATAAAGGTAATAGAGCCCT TCTGCCCCCCACCCACCAAATTTACACAACAAAATGACATGTTCGAATGTGAAAGGTCAT AATAGCTTTCCCATCATGAATCAGAAAGATGTGGACAGCTTGATGTTTTAGACAACCACT GAACTAGATGACTGTTGTACTGTAGCTCAGTCATTTAAAAAATATATAAATACTACCTTG TAGTGTCCCATACTGTGTTTTTTACATGGTAGATTCTTATTTAAGTGCTAACTGGTTATT TTCTTTGGCTGGTTTATTGTACTGTTATACAGAATGTAAGTTGTACAGTGAAATAAGTTA TTAAAGCATGTGTAAACATTGTTATATATCTTTTCTCCTAAATGGAGAATTTTGAATAAA ATATATTTGAAATTTT (SEQ ID NO: 10)

[0328] As used herein, the term "CASS4" refers to the gene encoding Cas scaffold protein family member 4. The terms "CASS4" and "Cas scaffold protein family member 4" include wild-type forms of the CASS4 gene, as well as variants of the wild-type CASS4 (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type CASS4 nucleic acid sequence (e.g., SEQ ID NO: 11, ENA Accession No. AJ276678). SEQ ID NO: 11 is the wild-type gene sequence encoding the CASS4 protein and is shown below. GAAGAGTGGTGTTTTTTTCTTCTTCTTCTTCTTTTGTGGTTTCACATAGCAAATGAGTGA CAGTCTCTACTTACAGACAAAGTGAGACGTCAGGCATTGAGACATAGCTCCATAGAATTC AGTTTCTGAGAACCAGCCAGAAGCATGCAGTGACATTGCACAATCTGCCTCTGAAGCTGG AGATACTAGCTGCAGAGCTCAGGGGAGCTGCTCCACATCACCGACATGAAGGGAACAGGC ATCATGGACTGTGCGCCCAAGGCACTCCTGGCCAGGGCACTTTATGACAACTGCCCTGAC TGCTCTGACGAGCTGGCTTTCAGCAGAGGGGACATCCTGACCATTCTGGAGCAACACGTG CCAGAAAGCGAGGGTTGGTGGAAGTGTTTGCTCCATGGGAGGCAAGGCCTGGCCCTGCC AACCGCCTCCAAATCCTCACGGAGGTCGCTGCAGACAGGCCGTGCCCCCCATTCCTGAGA GGCCTGGAAGAAGCTCCTGCCAGCTCAGAGGAGACCTATCAGGTGCCCACTCTACCCCGC CCTCCCACTCCAGGCCCCGTTTATGAGCAGATGAGGAGTTGGGCGGAGGGGCCCCAGCCC CCTACTGCCCAAGTCTATGAATTCCCCGACCCTCCCACCAGTGCCAGAATCATCTGTGAA AAGACTCTCAGCTTTCCAAAACAGGCCATCCTCACGCTTCCCAGACCTGTCCGGGCCTCA CTGCCGACTCTGCCTTCCCAGGTGTATGACGTGCCTACCCAGCACCGGGGCCCCGTGGTC CTGAAGGAGCCAGAGAAGCAGCAGTTATATGACATACCAGCCAGCCCCAAGAAGGCAGGA CTCCATCCCCCAGACAGCCAAGCAAGTGGGCAGGGTGTTCCCCTGATATCAGTGACTACC TTAAGAAGAGGCGGTTACAGCACATTACCAAATCCTCAGAAATCGGAATGGATTTATGAC ACTCCAGTGTCTCCAGGAAAGGCCAGCGTCAGAAACACGCCTCTCACCAGCTTTGCGGAA GAATCAAGGCCCCACGCTCTCCCCAGTTCCAGCTCCACTTTCTACAATCCTCCAAGTGGC AGATCCAGGTCCCTCACTCCACAACTGAATAACAATGTGCCCATGCAGAAAAAACTCAGC CTTCCAGAAATTCCTTCTTATGGCTTTCTTGTACCCAGAGGCACATTTCCTTTGGATGAA GATGTCAGCAACAAGGTTCCTTCAAGCTTCTCTGATTCCCCGAGTGGACAGCAGAACACC AAGCCCAATATAGACATCCCTAAAGCAACGTCGAGTGTTTCTCAGGCTGGGAAGGAGCTG GAGAAAGCCAAGGAGGTGTCAGAGAATTCCGCGGGCCATAATTCCTCATGGTTCTCCAGA CGGACAACTTCCCCATCTCCTGAACCGGACAGATTATCAGGTTCCAGTTCTGACAGCAGA GCTAGCATCGTTTCCTCGTGCTCCACCACATCCACCGACGACTCCTCCAGCTCTTCCTCG GAGGAGTCAGCAAAGGAGCTCTCCTTGGACCTGGATGTGGCCAAGGAGACAGTGATGGCT CTGCAGCACAAGGTGGTCAGCTCTGTCGCTGGCCTGATGCTCTTTGTCAGCAGGAAGTGG AGATTCCGAGACTATCTGGAGGCCAACATTGATGCAATCCACAGGTCCACTGATCACATA GAAGCCTCTGTAAGAGAATTTCTGGATTTTGCCCGAGGAGTCCATGGGACTGCCTGTAAC CTCACTGACAGTAACCTTCAGAACAGAATTCGGGACCAGATGCAGACCATCTCCAACTCC TACCGCATCCTGCTTGAAACAAAGGAAAGCTTGGATAATCGCAATTGGCCTCTGGAAGTT CTTGTGACTGACAGTGTCCAGAACAGCCCAGATGACCTTGAGAGGTTTGTCATGGTGGCA CGGATGCTTCCAGAAGACATCAAGAGGTTTGCCTCCATTGTCATTGCCAATGGAAGGCTC CTTTTTAAGCGGAACTGTGAAAAGGAAGAGACTGTGCAGTTGACCCCAAATGCAGAATTT AAGTGTGAAAAATACATCCAGCCTCCCCAAAGAGAAACTGAATCACACCAAAAGAGTACC CCTTCCACTAAGCAAAGGGAAGATGAACACTCTTCTGAACTATTAAAGAAAAATAGAGCA AATATCTGTGGACAGAATCCTGGCCCTCTTATACCTCAGCCTTCGAGTCAACAGACTCCT GAGAGGAAACCCCGCTTATCTGAACACTGCCGGCTGTACTTTGGGGCGCTCTTCAAAGCC ATCAGCGCATTTCACGGCAGCCTCAGCAGCAGCCAGCCCGCGGAGATCATCACTCAGAGC AAGCTGGTCATCATGGTGGGACAGAAGCTGGTGGACACGCTGTGCATGGAGACCCAGGAG AGGGACGTGCGCAATGAGATCCTCCGCGGCAGCAGTCACCTCTGCAGCCTGCTCAAGGAC GTAGCGCTGGCCACTAAGAATGCCGTGCTCACATACCCCAGCCCTGCCGCGCTGGGGCAC CTCCAGGCGGAGGCTGAGAAGCTGGAGCAACACACGCGGCAGTTCAGAGGGACACTGGGA TGAGGACTGTCTACCTCCCTTCCTCCTCTGCTCACC (SEQ ID NO: 11)

[0329] As used herein, the term "CCL5" refers to the gene encoding CC motif chemokine 5. The terms "CCL5" and "CC motif chemokine 5" include the wild-type form of the CCL5 gene, as well as variants of the wild-type CCL5 (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type CCL5 nucleic acid sequence (e.g., SEQ ID NO: 12, ENA Accession No. M21121). SEQ ID NO: 12 is the wild-type gene sequence encoding the CCL5 protein and is shown below. CCTCCGACAGCCTCTCCACAGGTACCATGAAGGTCTCCGCGGCACGCCTCGCTGTCATCC TCATTGCTACTGCCCTCTGCGCTCCTGCATCTGCCTCCCCATATTCCTCGGACACCACAC CCTGCTGCTTTGCCTACATTGCCCGCCCACTGCCCCGTGCCCACATCAAGGAGTATTTCT ACACCAGTGGCAAGTGCTCCAACCCAGCAGTCGTCTTTTGTCACCCGAAAGAACCGCCAAG TGTGTGCCAACCCAGAGAAGAAATGGGTTCGGGAGTACATCAACTCTTTGGAGATGAGCT AGGATGGAGAGTCCTTGAACCTGAACTTACACAAATTTGCCTGTTTCTGCTTGCTCTTGT CCTAGCTTGGGAGGCTTCCCTCACTATCCTACCCCACCCGCTCCTTGAAGGGCCCAGAT TCTGACCACGACGAGCAGCAGTTACAAAAACCTTCCCCAGGCTGGACGTGGTGGCTCAGC CTTGTAATCCCAGCACTTTGGGAGGCCAAGGTGGGTGGATCACTTGAGGTCAGGAGTTCG AGACAGCCTGGCCAACATGATGAAACCCCATGTGTACTAAAAATACAAAAAATTAGCCGG GCGTGGTAGCGGGCGCCTGTAGTCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATGGCGT GAACCCGGGAGCGGAGCTTGCAGTGAGCCGAGATCGCGCCACTGCACTCCAGCCTGGGCG ACAGAGCGAGACTCCGTCTCAAAAAAAAAAAAAAAAAAAAAAAAAATACAAAAATTAGCC GCGTGGTGGCCCACGCCTGTAATCCCAGCTACTCGGGAGGCTAAGGCAGGAAAATTGTTT GAACCCAGGAGGTGGAGGCTGCAGTGAGCTGAGATTGTGCCACTTCACTCCAGCCTGGGT GACAAAGTGAGACTCCGTCACAACAACAACAACAAAAAGCTTCCCCAACTAAAGCCTAGA AGAGCTTCTGAGGCGCTGCTTTGTCAAAAGGAAGTCTCTAGGTTCTGAGCTCTGGCTTTG CCTTGGCTTTGCAAGGGCTCTGTGACAAGGAAGGAAGTCAGCATGCCTCTAGAGGCAAGG AAGGGAGGAACACTGCACTCTTAAGCTTCCGCCGTCTCAACCCCTCACAGGAGCTTACTG GCAAACATGAAAAATCGGGG (SEQ ID NO: 12)

[0330] As used herein, the term "CD2AP" refers to a gene encoding a CD2-associated protein. The terms "CD2AP" and "CD2-associated protein" include wild-type forms of the CD2AP gene, as well as variants of the wild-type CD2AP (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type CD2AP nucleic acid sequence (e.g., SEQ ID NO: 13, ENA Accession No. AF146277). SEQ ID NO:13 is the wild-type gene sequence encoding the CD2AP protein and is shown below. GGAATTCCGGGAGGAGCGGACGTCGGCTTCTCCCCGCGGAGCCCCCAGCATGGTTGACT ATATTGTGGAGTATGACTATGATGCTGTACATGATGATGAATTAACTATTCGAGTTGGAG AAATCATCAGGAATGTGAAAAAGCTACAGGAGGAAGGGTGGCTGGAAGGAGAACTAAATG GGAGAAGAGGAATGTTCCCTGACAATTTCGTTAAGGAAATTAAAAGAGAGACGGAATTCA AGGATGACAGTTTGCCCATCAAACGGGAAAGGCATGGGAATGTAGCAAGTCTTGTACAAC GAATAAGCACCTATGGACTTCCAGCTGGAGGAATTCAGCCACATCCACAAACCAAAAACA TTAAGAAGAAGACCAAGAAGCGTCAGTGTAAAGTTCTTTTTGAGTACATTCCACAAAATG AGGATGAACTGGAGCTGAAAGTGGGAGATATTATTGATATTAATGAAGAGGTAGAAGAAG GCTGGTGGAGTGGAACCCTGAATAACAAGTTGGGACTGTTTCCCTCAAATTTTGTGAAAG AATTAGAGGTAACAGATGATGGTGAAACTCATGAAGCCCAGGACGATTCAGAAACTGTTT TGGCTGGGCCTACTTCACCTATACCTTCTCTGGGAAATGTGAGTGAAACTGCATCTGGAT CAGTTACACAGCCAAAGAAAATTCGAGGAATTGGATTTGGAGACATTTTTAAAGAAGGTT CTGTGAAACTTCGGACAAGAACATCCAGTAGTGAAACAGAAGAGAAAAAACCAGAAAAGC CCTTAATCCTACAGTCACTGGGACCCAAAACTCAGAGTGTGGAGATAACAAAAACAGATA CCGAAGGTAAAATTAAAGCTAAAGAATATTGTAGAACATTATTTGCCTATGAAGGTACTA ATGAAGATGAACTTACTTTTAAAGAGGGGGAGATAATCCATTTGATAAGTAAGGAGACTG GAGAAGCTGGCTGGTGGAGGGGCGAACTTAATGGTAAAGAAGGAGTATTTCCAGACAATT TTGCTGTCCAGATAAATGAACTTGATAAAGACTTTCCAAAACCAAAGAAACCACCACCTC CTGCTAAGGCTCCAGCTCCAAAGCCTGAACTGATAGCTGCAGAGAAGAAATATTTTTCTT TAAAGCCTGAAGAAAAGGATGAAAAATCAACACTGGAACAGAAACCTTCTAAACCAGCAG CTCCACAAGTCCCACCCAAGAAACCTACTCCACCTACCAAAGCCAGTAATTTATTGAGAT CTTCTGGAACAGTGTACCCAAAGCGACCTGAAAAACCAGTTCCTCCACCACCTCCTATAG CCAAGATTAATGGGGAAGTTTCTAGCATTTCATCAAAATTTGAAACTGAGCCAGTATCAA AACTAAAGCTAGATTCTGAACAGCTGCCCCTTAGACCAAAATCAGTAGACTTTGATTCAC TTACAGTAAGGACCTCCAAAGAAACAGATGTTGTAAATTTTGATGACATAGCTTCCTCAG AAAACTTGCTTCATCTCACTGCAAATAGACCAAAGATGCCTGGAAGAAGGTTGCCGGGCC GTTTCAATGGTGGACATTCTCCAACTCACAGCCCCGAAAAAATCTTGAAGTTACCAAAAG AAGAAGACAGTGCCAACCTGAAGCCATCTGAATTAAAAAAAGATACATGCTACTCTCCAA AGCCATCTGTGTACCTTTCAACACCTTCCAGTGCTTCTAAAGCAAATACAACTGCTTTCC TGACTCCATTAGAAATCAAAGCTAAAGTGGAAACAGATGATGTGAAAAAAAATTCCCTGG ATGAACTTAGAGCCCAGATTATTGAATTGTTGTGCATTGTAGAAGCACTGAAAAAGGATC ACGGGAAAGAACTGGAAAAACTGCGAAAAGATTTGGAAGAAGAGAAGACAATGAGAAGTA ATCTAGAGATGGAAATAGAGAAGCTGAAAAAAGCTGTCCTGTCTTCTTGAGTGGTGTGGA CCTGGTGTTCATAATGTTCCAGGGATTCAGAAGCAACGCTATGAACTTCAGCTGACTTGT TACTTAAAAAATTGTGAATTCTGTTGTTGTGATAAATATGAGCAAATGAAGTGTAATATCT ATAGAAAAGTAGAGTGAGGGTGAATTTATATATATTTTGTTTTGCCAATATGAAGAAA AAGAGGCCTTATTTCTTAACTGTGCTGGGATTGCAAACACTTTTTAAAAATTGTTTGCT TGAAAATACTACTGAATATAAATAAGATGTGCTCAGTAGTTTTTTATTGAAACTTGTA TTATTTTTAAAGAGATCTATACTATAAATATGGTGATATATTTACAAAGTAATCTGTATAA TATACTATTTGAGAGGGACAGATTAGCCTTTTTAGTAACTATAGTCACTACTTTTTCCATA ATGCATAAGGGATAAAACTCTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT ATATATATATATATTTTTTACTTTTATCCTCTTACCGAAGGTTACACTGTTGTGCCTGT TTGTCTGCAATGCTGTTTATATTTGGGTGATGAAATAGGGTTCCTTAGCTATATAAAC CAGATTACTCACCCATGCATATAGAGAACTAAATGAATATCAAAAATAATTTCATCAAC TTTTAGAATTTTAGTTGCTTGCACTATAGGAGTCATAAAAGGAACTTAGTTAAAATA TGTTGGATTGTTAAACATTTGGGGAAATATGAACTGTATTTTAAATTGTTAGGTCTGAA AAATCTAAAACTGTTAATTTAACCCTTAACTTGTGCCTAGAAACTACAGCACATATAAAAA TATGTAAACACCAGCCTGTTGCTGTACTTTTCTGCTTATTTTACAGCCTCAAATATTTCT CATTATCTTGTCACTTAGTTCTTCATGTTTCTCCTTCTGACTTTTAATAATGGTAATAGG AAAACAACCCAAAGCTTTTCAAACTTCAGGTGTGAGGTTTCCTATTTTGACAAGTTAAC TTGTAAATACTCAGGTTTTACGATGTATAATTTACCTAATAGACCAAACTAACTCATGGA GATATTTTGAACTATTATTTAGGTACAAACTTTATAAAGAATGTTAGTAGTCATAAAAT ATAACATTACAGCTTATTTAAAACCAAATATATTGAACATATTTTAAAATACATTTCACA GAATGGATGAATTAGTTGTTTCTTCAAAAGTTACTTATGAACAGTTGAATGCCTTTAAAA TGTTCTGTCTGTAGGTACATCTAAAAACACAAGTGGGTTTATTTAAATTTTTAAAATTTG AAATTTTTTATTTGCCAAAAATTGTTTTATGCTTTATTATATCGCAAATGAGTGTCAGAT TTTTGAGTACCAATGATCATGCTTCCATTTTTTTTAGTTTTAAACCACCAAACCAATATT TTTTCCTTTAAATTTTAATCTTATAATATAGAAATCTTATGTTAATGAAATTTTGTCATGT TTCAAATAAAGAAAACTGAAGTAGAAAATAGAAATGCCAGTAAACAACATAATGTTTAAT TTACAACTTACATTAGGGGTTTGGGGGGAATGCTAATTATATATTGAGAATATACATTAGA ACTCTTCAAAATGGGCTCTTCTAATGAGGTCACTACTGAACAAAATTGTTCCTCTTCTG TTAAATAGAATAGGTTTAAATGACTAGTCAAATGAATTATTTTCTCCTTGTTAAATAAAT TAAATCTTACTTTCTTTTAATGACCAACCTTAGGTAAAACAAAAATATTGTAATCCTAGA AATTATCCTCCAGCTTTCTCACCTGAAAATCTATTGAAGTGATTCCCTGGTCATCCTAATA ATGGGATGAGGGAAGTTTCCAGCAGATTTCAGGCTGTTCTTAAAGTTTTTGTTGGTCATT TTCTCAATAGTACATGAAATCAAGATGCTTATGAGCATGGAAATGTATTTAAAGTTTTTG CTTGTGTCCTCCTCAGTCAGAATAGAAAAGTAACTGAAATACTCTTACCTTTCTGTCCTT GATAAAATAGTAAAGAAAACCAAACAAACCCAGGCCTGATGGGAAATTGATTCCTTTAT TCTAGCAATTACTTTCTGTTGGTATGGGAAATGTTATTAATTTCTATTACTAAAGTTCAT ATCACAAAATGATATTTAATAATAACCTTGGGGTAAATCATGAATTTTTTTTTCTACGTG TGAGTATAAAAGACAAAAGTTGAACAGCATGGAATCTTCATTGCCAAAATTATTAGTGAAT GTATAGTTCAGGTATTCTTTGAGACACACAGTATCATTAATTTCCGAATTGTATTTCAGT GTTATTTTTTGTTTGTGACCACTAAGCTTCTGTCTTAATACAAAGCTGTTACCTTCTACA GAATTTAAGTCTGAAGATGTAAAGAGAGAACAGGCCTTGTGTAACAGAAGATACTCTTTT TTATGCTCCTTACTGTGATCACAGAAAAATTAAAAAATCCAAGTGCTCTCTAGATTTGTTG ATAAACATTTTATGCTTGCATTTAAACTTGAAATGTATGAGCAGAATGAGACAATCAGTT AAATCAGAAATGAGAAGTATTATAATGTAAAGGCCTTGTTTTGCTGTAGCAATAAAATGA CCAAGTGCAATGACTTGATTTAATAAAATCCGGAATTC (SEQ ID NO:13)

[0331] As used herein, the term "CD33" refers to the gene encoding the myeloid cell surface antigen CD33. The terms "CD33" and "myeloid cell surface antigen CD33" include wild-type forms of the CD33 gene, as well as variants of the wild-type CD33 (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type CD33 nucleic acid sequence (e.g., SEQ ID NO: 14, ENA Accession No. M23197). SEQ ID NO: 14 is the wild-type gene sequence encoding the CD33 protein and is shown below. GCTTCCTCAGACATGCCGCTGCTGCTACTGCTGCCCCTGCTGTGGGCAGGGGCCTGGCT ATGGATCCAAATTTCTGGCTGCAAGTGCAGGAGTCAGTGACGGTACAGGAGGGTTTGTGC GTCCTCGTGCCCTGCACTTTCTTCCATCCCATACCCTACTACGACAAGAACTCCCCAGTT CATGGTTACTGGTTCCGGGAAGGAGCCATTATATCCGGGGACTCTCCAGTGGCCACAAAC AAGCTAGATCAAGAAGTACAGGAGGAGACTCAGGGCAGATTCCGCCTCCTTGGGGATCCC AGTAGGAACAACTGCTCCCTGAGCATCGTAGACGCCAGGAGGAGGGATAATGGTTCATAC TTCTTTCGGATGGAGAGAGGAAGTACCAAATACAGTTACAAATCTCCCCAGCTCTCTGTG CATGTGACAGACTTGACCCACAGGCCCAAAATCCTCATCCCTGGCACTCTAGAACCCGGC CACTCCAAAAACCTTACCTGCTCTGTGTCCTGGGCCTGTGAGCAGGGAACACCCCCGATC TTCTCCTGGTTGTCAGCTGCCCCCACCTCCCTGGGCCCCAGGACTACTCACTCCTCGGTG CTCATAATCACCCCACGGCCCCAGGACCACGGCACCAACCTGACCTGTCAGGTGAAGTTC GCTGGAGCTGGTGTGACTACGGAGAGAACCATCCAGCTCAACGTCACCTATGTTCCACAG AACCCAACAACTGGTATCTTTCCAGGAGATGGCTCAGGGAAACAAGAGACCAGAGCAGGA CTGGTTCATGGGGCCATTGGAGGAGCTGGTGTTACAGCCCTGCTCGCTCTTTGTCTCTGC CTCATCTTCTTCATAGTGAAGACCCACAGGAGGAAAGCAGCCAGGACAGCAGTGGGCAGC AATGACACCCACCCTACCACAGGGTCAGCCTCCCCGAAACACCAGAAGAACTCCAAGTTA CATGGCCCCACTGAAACCTCAAGCTGTTCAGGTGCCGCCCCTACTGTGGAGATGGATGAG GAGCTGCATTATGCTTCCCTCAACTTTCATGGGATGAATCCTTCCAAGGACACCTCCACC GAATACTCAGAGGTCAGGACCCAGTGAGGAACCCTCAAGAGCATCAGGCTCAGCTAGAAG ATCCACATCCTCTACAGGTCGGGGACCAAAGGCTGATTCTTGGAGATTTAACTCCCCACA GGCAATGGGTTTATAGACATTATGTGAGTTTCCTGCTATATTAACATCATCTTGAGACTT TGCAAGCAGAGAGTCGTGGAATCAAATCTGTGCTCTTTCATTTGCTAAGTGTATGATGTC ACACAAGCTCCTTAACCTTCCATGTCTCCATTTTCTTCTCTGTGAAGTAGGTATAAGAAG TCCTATCTCATAGGGATGCTGTGAGCATTAAATAAAGGTACACATGGAAAACACCAG (SEQ ID NO: 14)

[0332] As used herein, the term "CD68" refers to the gene encoding the CD68 molecule. The terms "CD68" and "CD68 molecule" include wild-type forms of the CD68 gene, as well as variants of the wild-type CD68 (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type CD68 nucleic acid sequence (e.g., SEQ ID NO: 15, NCBI Reference Sequence: NM_001251.2). SEQ ID NO: 15 is the wild-type gene sequence encoding the CD68 protein and is shown below. (SEQ ID NO:15)

[0333] As used herein, the term "CLPTM1" refers to the gene encoding the CLPTM1 regulator of GABA type A receptor forward trafficking. The terms "CLPTM1" and "CLPTM1 regulator of GABA type A receptor forward trafficking" include the wild-type form of the CLPTM1 gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type CLPTM1. An example of such a variant is a nucleic acid having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type CLPTM1 nucleic acid sequence (e.g., SEQ ID NO: 16, NCBI Reference Sequence: NM_001294.3). SEQ ID NO: 16 is the wild-type gene sequence encoding the CLPTM1 protein, and is shown below. (SEQ ID NO:16)

[0334] As used herein, the term "CLU" refers to the gene encoding clusterin. The terms "CLU" and "clusterin" include wild-type forms of the CLU gene, as well as variants of the wild-type CLU (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type CLU nucleic acid sequence (e.g., SEQ ID NO: 17, ENA Accession No. M25915). SEQ ID NO:17 is the wild-type gene sequence encoding the CLU protein and is shown below. CTGCGAACCCTCTCTACTCTCCGAAGGGAATTGTCCTTCCTGGCTTCCACTACTTCCACC CCTGAATGCACAGGCAGCCCGGCCCAAGTCTCCCACTAGGGATGCAGATGGATTCGGTGT GAAGGGCTGGCTGCTGTTGCCTCCGGCTCTTGAAAGTCAAGTTCAGAGGCGTGCAAAGAC TCCAGAATTGGAGGCATGATGAAGACTCTGCTGCTGTTTGTGGGGCTGCTGCTGACCTGG GAGAGTGGGCAGGTCCTGGGGGACCAGACGGTCTCAGACAATGAGCTCCAGGAAATGTCC AATCAGGGAAGTAAGTACGTCAATAAGGAAATTCAAAAATGCTGTCAACGGGGTGAACAG ATAAAGACTCTCATAGAAAAAACAAACGAAGAGCGCAAGACACTGCTCAGCAACCTAGAA GAAGCCAAGAAGAAGAAGAAGAGGATGCCCTAAATGAGACCAGGGAATCAGAGACAAAGCTG AAGGAGCTCCCAGGAGTGTGCAATGAGACCATGATGGCCCTCTGGGGAAGAGGTGAAGCCCC TGCCTGAAACAGACCTGCATGAAGTTCTACGCACGCGTCTGCAGAAGTGGCTCAGGCCTG GTTGGCCGCCAGCTTGAGGAGTTCCTGAACCAGAGCTCGCCCTTCACTTCTGGATGAAT GGTGACCGCATCGACTCCCTGCTGGAGAACGACCGGCAGCAGACGCACATGCTGGATGTC ATGCAGGACCACTTCAGCCGCGCGTCCAGCATCATAGACGAGCTCTTCCAGGACAGGTTC TTCACCCGGGAGCCCCAGGATACCTACCACTACCTGCCCTTCAGCCTGCCCCACCGGAGG CCTCACTTCTTCTTTCCCAAGTCCCGCATCGTCCGCAGCTTGATGCCCTTCTCTCCGTAC GAGCCCCTGAACTTCCACGCCATGTTCCAGCCCTTCCTTGAGATGATACACGAGGCTCAG CAGGCCATGGACATCCACTTCCACAGCCCGGCCTTCCAGCACCGCCAACAGAATTCATA CGAGAAGGCGACGATGACCGGACTGTGTGCCGGGAGATCCCGCCACAACTCCACGGGCTGC CTGCGGATGAAGGACCAGTGTGCAAGTGCCGGGAGATCTTGTCTGTGGACTGTTCCACC AACAACCCCTCCCAGGCTAAGCTGCGGCGGGAGCTCGACGAATCCCTCCAGGTCGCTGAG AGGTTGACCAGGAAATATAACGAGCTGCTAAAGTCCTACCAGTGGAAGATGCTCAACACC TCCTCCTTGCTGGAGCAGCTGAACGAGCAGTTTAACTGGGTGTCCCGGCTGGCAAACCTC ACGCAAGGCGAAGACCAGTACTATCTGCGGGTCACCACGGTGGCTTCCCACACTTCTGAC TCGGACGTTCCTTCCGGTGTCACTGAGGTGGTCGTGAAGCTCTTTGACTCTGATCCCATC ACTGTGACGGTCCCTGTAGAAGTCTCCAGGAAGAACCCTAAATTTATGGAGACCGTGGCG GAGAAAGCGCTGCAGGAATACCGCAAAAAGCACCGGGAGGAGTGAGATGTGGATGTTGCT TTTGCACCTACGGGGGCATCTGAGTCCAGCTCCCCCCAAGATGAGCTGCAGCCCCCCAGA GAGAGCTCTGCACGTCACCAAGTAACCAGGC (SEQ ID NO:17)

[0335] As used herein, the term "CR1" refers to a gene encoding complement receptor type 1. The terms "CR1" and "complement receptor type 1" include wild-type forms of the CR1 gene, as well as variants of the wild-type CR1 (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type CR1 nucleic acid sequence (e.g., SEQ ID NO: 18, ENA Accession No. Y00816). SEQ ID NO:18 is the wild-type gene sequence encoding the CR1 protein and is shown below. CGTGGTTTGTAGATGTGCTTGGGGAGAATGGGGGCCTCTTCTCCAAGAAGCCCGGAGCCT GTCGGGCCGCCGGCGCCCGGTCTCCCCTTCTGCTGCGGAGGATCCCTGCTGGCGGTTGTG GTGCTGCTTGCGCTGCCGGTGGCCTGGGGTCAATGCAATGCCCCAGAATGGCTTCCATTT GCCAGGCCTACCAACCTAACTGATGAGTTTGAGTTTCCCATTGGGACATATCTGAACTAT GAATGCCGCCCTGGTTATTCCGGAAGACCGTTTTCTATCATCTGCCTAAAAAACTCAGTC TGGACTGGTGCTAAGGACAGGTGCAGACGTAAATCATGTCGTAATCCTCCAGATCCTGTG AATGGCATGGTGCATGTGATCAAAGGCATCCAGTTCGGATCCCAAATTAAATATTCTTGT ACTAAAGGATACCGACTCATTGGTTCCTCGTCTGCCACATGCATCATCTCAGGTGATACT GTCATTTGGGATAATGAAACACCTATTTGTGACAGAATTCCTTGTGGGCTACCCCCCACC ATCACCAATGGAGATTTCATTAGCACCAACAGAGAGAATTTTCACTATGGATCAGTGGTG ACCTACCGCTGCAATCCTGGAAGCGGAGGGAGAAAGGTGTTTGAGCTTGTGGGTGAGCCC TCCATATACTGCACCAGCAATGACGATCAAGTGGGCATCTGGAGCGGCCCCGCCCCTCAG TGCATTATACCTAACAAATGCACGCCTCCAAATGTGGAAAATGGAATATTGGTATCTGAC AACAGAAGCTTATTTTCCTTAAATGAAGTTGTGGAGTTTAGGTGTCAGCCTGGCTTTGTC ATGAAAGGACCCCGCCGTGTGAAGTGCCAGGCCCTGAACAAATGGGAGCCGGAGCTACCA AGCTGCTCCAGGGTATGTCAGCCACCTCCAGATGTCCTGCATGCTGAGCGTACCCAAAGG GACAAGGACAACTTTTCACCTGGGCAGGAAGTGTTCTACAGCTGTGAGCCCGGCTACGAC CTCAGAGGGGCTGCGTCTATGCGCTGCACACCCCAGGGAGACTGGAGCCCTGCAGCCCCC ACATGTGAAGTGAAATCCTGTGATGACTTCATGGGCCAACTTCTTAATGGCCGTGTGCTA TTTCCAGTAAATCTCCAGCTTGGAGCAAAAGTGGATTTTGTTTGTGATGAAGGATTTCAA TTAAAAGGCAGCTCTGCTAGTTACTGTGTCTTGGCTGGAATGGAAAGCCTTTGGAATAGC AGTGTTCCAGTGTGTGAACAAATCTTTTGTCCAAGTCCTCCAGTTATTCCTAATGGGAGA CACACAGGAAAACCTCTGGAAGTCTTTCCCTTTGGAAAAGCAGTAAATTACACATGCGAC CCCCACCCAGACAGAGGGACGAGCTTCGACCTCATTGGAGAGAGCACCATCCGCTGCACA AGTGACCCTCAAGGGAATGGGGTTTGGAGCAGCCCTGCCCCTCGCTGTGGAATTCTGGGT CACTGTCAAGCCCCAGATCATTTTCTGTTTGCCAAGTTGAAAACCCAAACCAATGCATCT GACTTTCCCATTGGGACATCTTTAAAGTACGAATGCCGTCCTGAGTACTACGGGAGGCCA TTCTCTATCACATGTCTAGATAACCTGGTCTGGTCAAGTCCCAAAGATGTCTGTAAACGT AAATCATGTAAAACTCCTCCAGATCCAGTGAATGGCATGGTGCATGTGATCACAGACATC CAGGTTGGATCCAGAATCAACTATTCTTGTACTACAGGGCACCGACTCATTGGTCACTCA TCTGCTGAATGTATCCTCTCGGGCAATGCTGCCCATTGGAGCACGAAGCCGCCAATTTGT CAACGAATTCCTTGTGGGCTACCCCCCACCATCGCCAATGGAGATTTCATTAGCACCAAC AGAGAGAATTTTCACTATGGATCAGTGGTGACCTACCGCTGCAATCCTGGAAGCGGAGGG AGAAAGGTGTTTGAGCTTGTGGGTGAGCCCTCCATATACTGCACCAGCAATGACGATCAA GTGGGCATCTGGAGCGGCCCGGCCCCTCAGTGCATTATACCTAACAAATGCACGCCTCCA AATGTGGAAAATGGAATATTGGTATCTGACAACAGAAGCTTATTTTCCTTAAATGAAGTT GTGGAGTTTAGGTGTCAGCCTGGCTTTGTCATGAAAGGACCCCGCCGTGTGAAGTGCCAG GCCCTGAACAAATGGGAGCCGGAGCTACCAAGCTGCTCCAGGGTATGTCAGCCACCTCCA GATGTCCTGCATGCTGAGCGTACCCAAAGGGACAAGGACAACTTTTCACCCGGGCAGGAA GTGTTCTACAGCTGTGAGCCCGGCTATGACCTCAGAGGGGCTGCGTCTATGCGCTGCACA CCCCAGGGAGACTGGAGCCCTGCAGCCCCCACATGTGAAGTGAAATCCTGTGATGACTTC ATGGGCCAACTTCTTAATGGCCGTGTGCTATTTCCAGTAAATCTCCAGCTTGGAGCAAAA GTGGATTTTGTTTGTGATGAAGGATTTCAATTAAAAGGCAGCTCTGCTAGTTATTGTGTC TTGGCTGGAATGGAAAGCCTTTGGAATAGCAGTGTTCCAGTGTGTGAACAAATCTTTTGT CCAAGTCCTCCAGTTATTCCTAATGGGAGACACACAGGAAAACCTCTGGAAGTCTTTCCC TTTGGAAAAGCAGTAAATTACACATGCGACCCCCACCCAGACAGAGGGACGAGCTTCGAC CTCATTGGAGAGAGCACCATCCGCTGCACAAGTGACCCTCAAGGGAATGGGGTTTGGAGC AGCCCTGCCCCTCGCTGTGGAATTCTGGGTCACTGTCAAGCCCCAGATCATTTTCTGTTT GCCAAGTTGAAAACCCAAACCAATGCATCTGACTTTCCCATTGGGACATCTTTAAAGTAC GAATGCCGTCCTGAGTACTACGGGAGGCCATTCTCTATCACATGTCTAGATAACCTGGTC TGGTCAAGTCCCAAAGATGTCTGTAAACGTAAATCATGTAAAACTCCTCCAGATCCAGTG AATGGCATGGTGCATGTGATCACAGACATCCAGGTTGGATCCAGAATCAACTATTCTTGT ACTACAGGGCACCGACTCATTGGTCACTCATCTGCTGAATGTATCCTCTCAGGCAATACT GCCCATTGGAGCACGAAGCCGCCAATTTGTCAACGAATTCCTTGTGGGCTACCCCCAACC ATCGCCAATGGAGATTTCATTAGCACCAACAGAGAGAATTTTCACTATGGATCAGTGGTG ACCTACCGCTGCAATCTTGGAAGCAGAGGGAGAAAGGTGTTTGAGCTTGTGGGTGAGCCC TCCATATACTGCACCAGCAATGACGATCAAGTGGGCATCTGGAGCGGCCCCGCCCCTCAG TGCATTATACCTAACAAATGCACGCCTCCAAATGTGGAAAATGGAATATTGGTATCTGAC AACAGAAGCTTATTTTCCTTAAATGAAGTTGTGGAGTTTAGGTGTCAGCCTGGCTTTGTC ATGAAAGGACCCCGCCGTGTGAAGTGCCAGGCCCTGAACAAATGGGAGCCAGAGTTACCA AGCTGCTCCAGGGTGTGTCAGCCGCCTCCAGAAATCCTGCATGGTGAGCATACCCCAAGC CATCAGGACAACTTTTCACCTGGGCAGGAAGTGTTCTACAGCTGTGAGCCTGGCTATGAC CTCAGAGGGGCTGCGTCTCTGCACTGCACACCCCAGGGAGACTGGAGCCCTGAAGCCCCG AGATGTGCAGTGAAATCCTGTGATGACTTCTTGGGTCAACTCCCTCATGGCCGTGTGCTA TTTCCACTTAATCTCCAGCTTGGGGCAAAGGTGTCCTTTGTCTGTGATGAAGGGTTTCGC TTAAAGGGCAGTTCCGTTAGTCATTGTGTCTTGGTTGGAATGAGAAGCCTTTGGAATAAC AGTGTTCCTGTGTGTGAACATATCTTTTGTCCAAATCCTCCAGCTATCCTTAATGGGAGA CACACAGGAACTCCCTCTGGAGATATTCCCTATGGAAAAGAAATATCTTACACATGTGAC CCCCACCCAGACAGAGGGATGACCTTCAACCTCATTGGGGAGAGCACCATCCGCTGCACA AGTGACCCTCATGGGAATGGGGTTTGGAGCAGCCCTGCCCCTCGCTGTGAACTTTCTGTT CGTGCTGGTCACTGTAAAACCCCAGAGCAGTTTCCATTTGCCAGTCCTACGATCCCAATT AATGACTTTGAGTTTCCAGTCGGGACATCTTTGAATTATGAATGCCGTCCTGGGTATTTT GGGAAAATGTTCTCTATCTCCTGCCTAGAAAACTTGGTCTGGTCAAGTGTTGAAGACAAC TGTAGACGAAAATCATGTGGACCTCCACCAGAACCCTTCAATGGAATGGTGCATATAAAC ACAGATACACAGTTTGGATCAACAGTTAATTATTCTTGTAATGAAGGGTTTCGACTCATT GGTTCCCCATCTACTACTTGTCTCGTCTCAGGCAATAATGTCACATGGGATAAGAAGGCA CCTATTTGTGAGATCATATCTTGTGAGCCACCTCCAACCATATCCAATGGAGACTTCTAC AGCAACAATAGAACATCTTTTCACAATGGAACGGTGGTAACTTACCAGTGCCACACTGGA CCGATGGAGAACAGCTGTTTGAGCTTGTGGGAGAACGGTCAATATATTGCACCAGCAAA GATGATCAAGTTGGTGTTTGGAGCAGCCCTCCCCTCGGTGTATTTCTACTAATAAATGC ACAGCTCCAGAAGTTGAAAATGCAATTAGAGTACCAGGAAACAGGAGTTTCTTTTCCCTC ACTGAGATCATCAGATTTAGATGTCAGCCCGGGTTTGTCATGGTAGGGTCCCACACTGTG CAGTGCCAGACCAATGGCAGATGGGGCCCAAGCTGCCACACTGCTCCAGGGTGTGTCAG CCGCCTCCAGAAATCCTGCATGGTGAGCATACCCTAAGCCATCAGGACAACTTTTCACCT GGGCAGGAAGTGTTCTACAGCTTGGAGCCCAGCTATGACCTCAGAGGGGCTGCGTCTCTG CACTGCACGCCCCAGGGAGACTGGAGCCCTGAAGCCCCTAGATGTACAGTGAAATCCTGT GATGACTTCCTGGGCCAACTCCCTCATGGCCGTGTGCTACTTCCACTTAATCTCCAGCTT GGGGCAAAGGTGTCCTTTGTTTGCGATGAAGGGTTCCGATTAAAAAGGCAGGTCTGCTAGT CATTGTGTCTTGGCTGGAATGAAAGCCCTTTGGAATAGCAGTGTTCCAGTGTGTGAACAA ATCTTTTGTCCAAATCCTCCAGCTATCCTTAATGGGAGACACACAGGAACTCCCTTTGGA GATATTCCCTATGGAAAGAAATATCTTACGCATGCGACACCCACCCAGACAGAGGGATG ACCTTCAACCTCATTGGGGAGAGCTCCATCCGCTGCACAAGTGACCCTCAAGGGAATGGG GTTTGGAGCAGCCTGCCCTCCGCTGTGAACTTTCTGTTCCTGCTGCCTGCCCACATCCA CCCAAGATCCAAAACGGGCATTACATTGGAGGACACGTATCTCTATATCTTCCTGGGATG ACAATCAGCTACACTTGTGACCCCGGCTACCTGTTAGTGGGAAAGGGCTTCATTTTCTGT ACAGACCAGGGAATCTGGAGCCAATTGGATCATTATTGCAAAAGAAATTGTAGCTTC CCACTGTTTATGAATGGAATCTCGAAGGAGTTAGAAATGAAAAAGTATATCACTATGGA GATTATGTGACTTTGAAGTGTGAAGATGGGTATACTCTGGAAGGCAGTCCCTGGAGCCAG TGCCAGGCGGATGACAGATGGGACCCTCCTCTGGCCAAATGTACCTCTCGTGCACATGAT GCTCTCATAGTTGGCACTTTATCTGGTACGATCTTCTTTTATTTACTCATCATTTTCCTC TCTTGGATAATTCTAAAGCACAGAAAAGGCAATAATGCACATGAAAACCCTAAAGAAGTG GCTATCCATTTACATTCTCAAGGAGGCAGCAGCGTTCATCCCCGAACTCTGCAAACAAAT GAAGAAAAATAGCAGGGTCCTTCCTTGACAAAGTACTATACAGCTGAAGAACATCTCGAAT ACAATTTTGGTGGGAAAGGAGCCAATTGATTTCAACAGAATCAGATCTGAGCTTCATAAA GTCTTTGAAGTGACTTCACAGAGACGCAGACATGTGCACTTGAAGATGCTGCCCCTTCCC TGGTACCTAGCAAAGCTCCTGCCTCTTTGTGTGCGTCACTGTGAAACCCCCACCCTTCTG CCTCGTGCTAAACGCACACAGTATCTAGTCAGGGGAAAAGACTGCATTTAGGAGATAGAA AATAGTTTGGATTACTTAAAGGAATAAGGTGTTGCCTGGAATTTCTGGTTTGTAAGGTGG TCACTGTTCTTTTTTAAAATATTTGTAATATGGAATGGGCTCAGTAAGAAGAGCTTGGAA AATGCAGAAAGTTATGAAAAATAAGTCACTTATAATTATGCTACCTACTGATAACCACTC CTAATATTTTGATTCATTTTCTGCCTATCTTCTTTCACATATGTGTTTTTTTACATACGT ACTTTTCCCCCCTTAGTTTGTTTCCTTTTATTTTATAGAGCAGAACCCTAGTCTTTTAAA CAGTTTAGAGTGAAATATATGCTATATCAGTTTTTACTTTCTCTAGGGAGAAAAATTAAT TTACTAGAAAGGCATGAAATGATCATGGGAAGAGTGGTTAAGACTACTGAAGAGAAATAT TTGGAAAATAAGATTTCGATATCTTCTTTTTTTTTGAGATGGAGTCTGGCTCTGTCTCCC AGGCTGGAGTGCAGTGGCGTAATCTCGGCTCACTGCAACGTCCGCCTCCCG (SEQ ID NO: 18)

[0336] As used herein, the term "CSF1" refers to the gene encoding macrophage colony-stimulating factor 1. The terms "CSF1" and "macrophage colony-stimulating factor 1" include the wild-type form of the CSF1 gene, as well as variants of the wild-type CSF1 (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type CSF1 nucleic acid sequence (e.g., SEQ ID NO: 19, ENA Accession No. M37435). SEQ ID NO: 19 is the wild-type gene sequence encoding the CSF1 protein and is shown below. CCTGGGTCCTCTCGGCGCCAGAGCCGCTCTCCGCATCCCAGGACAGCGGTGCGGCCCTCG GCCGGGGCGCCCACTCCGCAGCAGCCAGCGAGCCAGCTGCCCCGTATGACCGCGCCGGGC GCCGCCGGGCGCTGCCCTCCCACGACATGGCTGGGCTCCCTGCTGTTGTTGGTCTGTCTC CTGGCGAGCAGGAGTATCACCGAGGAGGTGTCGGAGTACTGTAGCCACATGATTGGGAGT GGACACCTGCAGTCTCTGCAGCGGCTGATTGACAGTCAGATGGAGACCTCGTGCCAAATT ACATTTGAGTTTGTAGACCAGGAACAGTTGAAAGATCCAGTGTGCTACCTTAAGAAGGCA TTTCTCCTGGTACAAGACATAATGGAGGACACCATGCGCTTCAGAGATAACACCGCCAAT CCCATCGCCATTGTGCAGCTGCAGGAACTCTCTTTGAGGCTGAAGAGCTGCTTCACCAAG GATTATGAAGAGCATGACAAGGCCTGCGTCCGAACTTTCTATGAGACACCTCTCCAGTTG CTGGAGAAGGTCAAGAATGTCTTTAATGAAACAAAAGAATCTCCTTGACAAGGACTGGAAT ATTTTCAGCAAGAACTGCAACAACAGCTTTGCTGAATGCTCCAGCCAAGATGTGGTGACC AAGCCTGATTGCAACTGCCTGTACCCCAAAGCCATCCTAGCAGTGACCCGCCTCTGTC TCCCCTCATCAGCCCCTCGCCCCCTCCATGGCCCCTGTGGCTGGCTTGACCTGGGAGGAC TCTGAGGGAACTGAGGGCAGCTCCCTCTTGCCTGGTGAGCAGCCCCTGCACACAGTGGAT CCAGGCAGTGCCAAGCAGCGGCCACCCAGGAGCACCTGCCAGAGCTTTGAGCCGCCAGAG ACCCCAGTTGTCAAGGACAGCACCATCGGTGGCTCACCACAGCCTCGCCCCTCTGTCGGG GCCTTCAACCCCGGGATGGAGGATATTCTTGACTCTGCAATGGGCACTAATTGGGTCCCA GAAGAAGCCTCTGGAGAGGCCAGTGAGATTCCCGATCCCAAGGGACAGAGCTTTCCCCC TCCAGGCCAGGAGGGGCAGCATGCAGACAGAGCCCGCCAGACCCAGCAACTTCCTTCCA GCATCTTCTCCACTCCCTGCATCAGCAAAGGGCCAACAGCCGGCAGATGTAACTGCTACA GCCTTGCCCAGGGTGGGCCCCGTGATCCCACTGGCCAGGACTGGAATCACACCCCCCCAG AAGACAGACCATCCATCTGCCCTGCTCAGAGACCCCCCGGAGCCAGGCTCTCCCAGGATC TCATCACTGCGCCCCCAGGCCCTCAGCAACCCCTCCACCTCTCTGCTCAGCCACAGCTT TCCAGAAGCCACTCCTCGGGCAGCGTGCTGCCCCTTGGGAGCTGGAGGGCAGGAGGAGC ACCAGGGATCGGACGAGCCCGCAGAGCCAGAAGCAGCACCAGCAAGTGAAGGGGCAGCC AGGCCCCTGCCCCGTTTTAACTCCGTTCCTTGACTGACACAGGCCATGAGAGGCAGTCC GAGGGATCCTCCAGCCCGCAGCTCCAGGAGTCTGTCTTCCACCTGCTGGTGCCCAGTGTC ATCCTGGTCTTGCTGGCTGTCGGAGGCCTCTTGTTCTCACAGGTGGAGGCGGCGGAGCCAT CAAGAGCCTCAGAGAGCGGGATTCTCCCTTGGAGCAACCAGAGGGCAGCCCCCTGACTCAG GATGACAGACAGGTGGAACTGCCAGTGTAGAGGGAATTCTAAGCTGGACGCACAGAACAG TCCTTCGTGGGAGGAGACATTATGGGGCGTCCACCACCACCCCTCCTGGCCATCCTCCC TGGAATGTGGTCTGCCCTCCACCAGAGCTCCTGCCTGCCAGGACTGGACCAGAGCAGCCA GGCTGGGGCCCCTCTGTCTCAACCCGCAGACCCTTGACTGAATGAGAGAGGCCAGAGGAT GCTCCCCATGCTGCCACTATTTATTGTGAGCCCTGGAGGCTCCCATGTGCTTGAGGAAGG CTGGTGAGCCCGGCTCAGGACCCTCTTCCCTCAGGGGCTGCAGCCTCCTCTCACTCCCTT CCATGCCGGAACCCAGGCCAGGGACCCACCGGCCTGTGGTTTGTGGGAAAGCAGGGTGCA CGCTGAGGAGTGAAACAACCCTGCACCCAGAGGGCCTGCCTGGTGCCAAGGTATCCCAGC CTGGACAGGCATGGACCTGTCTCCAGACAGAGGAGCCTGAAGTTCGTGGGGCGGGACAGC CTCGGCCTGATTTCCCGTAAAGGTGTGCAGCCTGAGAGACGGGAAGAGGAGGCCTCTGCA CCTGCTGGTCTGCACTGACAGCCTGAAGGGTCTACACCCTCGGCTCACCTAAGTCCCTGT GCTGGTTGCCAGGCCCAGAGGGGAGGCCAGCCCTGCCCTCAGGACCTGCCTGACCTGCCA GTGATGCCAAGAGGGGGATCAAGCACTGGCCTCTGCCCCTCCTCCTTCCAGCACCTGCCA GAGCTTCTCCAGCAGGCCAAGCAGAGGCTCCCCTCATGAAGGAAGCCATTGCACTGTGAA CACTGTACCTGCCTGCTGAACAGCCTCCCCCCGTCCATCCATGAGCCAGCATCCGTCCGT CCTCCACTCTCCAGCCTCTCCCCAGCCTCCTGCACTGAGCTGGCCTCACCAGTCGACTGA GGGAGCCCCTCAGCCCTGACCTTCTCCTGACCTGGCCTTTGACTCCCCGGAGTGGAGTGG GGTGGGAGAACCTCCTGGGCCGCCAGCCAGAGCCGCTCTTTAGGCTGTGTTCTTCGCCCA GGTTTCTGCATCTTCCACTTTGACATTCCCAAGAGGGAAGGGACTAGTGGGAGAGAGCAA GGGAGGGGAGGGCACAGACAGAGAGCCTACAGGGCGAGCTCTGACTGAAGATGGGCCTTT GAAATATAGGTATGCACCTGAGGTTGGGGGAGGGTCTGCACTCCCAAACCCCAGCGCAGT GTCCTTTCCCTGCTGCCGACAGGAACCTGGGGCTGAGCAGGTTATCCCTGTCAGGAGCCC TGGACTGGGCTGCATCTCAGCCCCACCTGCATGGTATCCAGCTCCCATCCACTTCTCACC CTTCTTTCCTCCTGACCTTGGTCAGCAGTGATGACCTCCAACTCTCACCCACCCCCTCTA CCATCACCTCTAACCAGGCAAGCCAGGGTGGGAGAGCAATCAGGAGAGCCAGGCCTCAGC TTCCAATGCCTGGAGGGCCTCCACTTTGTGGCCAGCCTGTGGTGCTGGCTCTGAGGCCTA GGCAACGAGCGACAGGGCTGCCAGTTGCCCCTGGGTTCCTTTGTGCTGCTGTGTGCCTCC TCTCCTGCCGCCCTTTGTCCTCCGCTAAGAGACCCTGCCCTACCTGGCCGCTGGGCCCCG TGACTTTCCCTTCCTGCCCAGGAAAGTGAGGGTCGGCTGGCCCCACCTTCCCTGTCCTGA TGCCGACAGCTTAGGGAAGGGCACTGAACTTGCATATGGGGCTTAGCCTTCTAGTCACAG CCTCTATATTTGATGCTAGAAAACACATATTTTTAAATGGAAGAAAAATAAAAAGGCATT CCCCCTTCATCCCCCTACCTTAAACATATAATATTTTAAAGGTCAAAAAAGCAATCCAAC CCACTGCAGAAGCTCTTTTTGAGCACTTGGTGGCATCAGAGCAGGAGGAGCCCCAGAGCC ACCTCTGGTGTCCCCCAGGCTACCTGCTAGGAACCCCTTCTGTTCTCTGAGAACTCAAC AGAGGACATTGGCTCACGCACTGTGAGATTTTGTTTTTATACTTGCAACTGGTGAATTAT TTTTTATAAAGTCATTTAATATCTATTTAAAAGATAGGAAGCTGCTTATATATTTAATA ATAAAAGAAGTGCACAAGCTGCCGTTGACGTAGCTCGAG (SEQ ID NO:19)

[0337] As used herein, the term "CST7" refers to a gene encoding cystatin-F. The terms "CST7" and "cystatin-F" include wild-type forms of the CST7 gene, as well as variants of the wild-type CST7 (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type CST7 nucleic acid sequence (e.g., SEQ ID NO: 20, ENA Accession No. AF031824). SEQ ID NO:20 is the wild-type gene sequence encoding the CST7 protein and is shown below. GGCTCAGCACAGGCACAAACCATTGCCCGGCACTGGCCCGTGCTGCCTGAGAAGGATTGG CACGGGCACAGACCACTGCCCCCACCTGCCCTGCGCCATCTACCCAAGAAGGCTCGGCAC GGGCACCAACCACTGCCTCCAACTGCCCCATGCTGCCTGAGAAGGCACTGCACGGCCACC CCCAACTGCCCCGCACTGTCCCTACCCGGGCAGCCATGCGAGCGGCTGGAACTCTGCTGG CCTTCTGCTGCCTGGTCTTGAGCACCACTGGGGGCCCTTCCCCAGATACTTGTTCCCAGG ACCTTAACTCACGTGTGAAGCCAGGATTTCCTAAAACAATAAAGACCAATGACCCAGGAG TCCTCCAAGCAGCCAGATACAGTGTTGAAAAGTTCAACAACTGCACGAACGACATGTTCT TGTTCAAGGAGTCCCGCATCACAAGGGCCCTAGTTCAGATAGTGAAAGGCCTGAAATATA TGCTGGAGGTGGAAATTGGCAGAACTACCTGCAAGAAAAACCAGCACCTGCGTCTGGATG ACTGTGACTTCCAAACCAACCACACCTTGAAGCAGACTCTGAGCTGCTACTCTGAAGTCT GGGTCGTGCCCTGGCTCCAGCACTTCGAGGTGCCTGTTCTCCGTTGTCACTGACCCCCGC CTCTTCAGCAAGACCACAGCCATGACAAACACCAGGATGCATGCTCCTTGTCCCCTCCCA CCCGCCTCATGACCCAGCCTCACAGACCCTCTCAGGCCTCTGACGAGTGAGCGGGTGAAG TGCCACTGGGTCACCGCAGGGCAGCTGGAATGGCAGCATGGTAGCACCTCCTAACAGATT AAATAGATCACATTTGCTTCTAAAATT (SEQ ID NO: 20)

[0338] As used herein, the term "CTSB" refers to the gene encoding cathepsin B. The terms "CTSB" and "cathepsin B" include wild-type forms of the CTSB gene, as well as variants of wild-type CTSB (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type CTSB nucleic acid sequence (e.g., SEQ ID NO: 21, ENA Accession No. M14221). SEQ ID NO:21 is the wild-type gene sequence encoding the CTSB protein and is shown below. AATTCCGCGGCAACCGCTCGGCAACGCCAACCGCTCCGCTGCGCGCAGGCTGGGCTGCA GGCTCTCGGCTGCAGCGCTGGGCTGGTGTGCAGTGGTGCGACCACGGCTCACGGCAGCCT CAGCCACCCAGATGTAAGCGATCTGGTTCCCACCTCAGCCTTCCGAGTAGTGGATCTAGG ATCTGGCTTCCAACATGTGGCAGCTCTGGGCCTCCCTCTGCTGCCTGCTGGTGTTGGCCA ATGCCCGGAGCAGGCCCTCTTTCCATCCCGTGTCGGATGAGCTGGTCAACTATGTCAACA AACGGAATACCACGTGGCAGGCCGGGCACAACTTCTACAACGTGGACATGAGCTACTTGA AGAGGCTATGTGGTACCTTCCTGGGTGGGCCCAAGCCACCCCAGAGAGTTATGTTTACCG AGGACCTGAAGCTGCCTGCAAGCTTCGATGCACGGGAACAATGGCCACAGTGTCCCACCA TCAAAGAGATCAGAGACCAGGGCTCCTGTGGCTCCTGCTGGGCCTTCGGGGCTGTGGAAG CCATCTCTGACCGCATCTGCATCCACACCAATGCGCACGTCAGCGTGGAGGTGTCGGCGG AGGACCTGCTCACCTGCTGTGGCAGCATGTGTGGGGACGGCTGTAATGGTGGCTATCCTG CTGAAGCTTGGAACTTCTGGACAAGAAAAGGCCTGGTTTCTGGTGGCCTCTATGAATCCC ATGTAGGGTGCAGACCGTACTCCATCCCTCCCTGTGAGCACCACGTCAACGGCTCCCGGC CCCCATGCACGGGGGAGGGAGATACCCCCAAGTGTAGCAAGATCTGTGAGCCTGGCTACA GCCCGACCTACAAACAGGACAAGCACTACGGATACAATTCCTACAGCGTCTCCAATAGCG AGAAGGACATCATGGCCGAGATCTACAAAAACGGCCCCGTGGAGGGAGCTTTCTCTGTGT ATTCGGACTTCCTGCTCTACAAGTCAGGAGTGTACCAACACGTCACCGGAGAGATGATGG GTGGCCATGCCATCCGCATCCTGGGCTGGGGAGTGGAGAATGGCACACCCTACTGGCTGG TTGCCAACTCCTGGAACACTGACTGGGGTGACAATGGCTTCTTTAAAATACTCAGAGGAC AGGATCACTGCGGAATCGAATCAGAAGTGGTGGCTGGAATTCCACGCACCGATCAGTACT GGGAAAAGATCTAATCTGCCGTGGGCCTGTCGTGCCAGTCCTGGGGGCGAGATCGGGGTA GAAAGTCATTTTATTCTTTAAGTTCACGTAAGATACAAGTTTCAGGCAGGGTCTGAAGGA CTGGATTGGCCAAAGTCCTCCAAGGAGACCAAGTCCTGGCTACATCCCAGCCTGTGGTTA CAGTGCAGACAGGCCATGTGAGCCACCGCTGCCAGCACAGAGCGTCCTTCCCCCTGTAGA CTAGTGCCGTGGGAGTACCTGCTGCCCAGCTGCTGTGGCCCCCTCCGTGATCCATCCATC TCCAGGGAGCAAGACAGAGACGCAGGATGGAAAGCGGAGTTCCTAACAGGATGAAAGTTC CCCCATCAGTTCCCCCAGTACCTCCAAGCAAGTAGCTTTCCACATTTGTCACAGAAATCA GAGGAGAGATGGTGTTGGGAGCCCTTTGGAGAACGCCAGTCTCCAGGTCCCCCTGCATCT ATCGAGTTTGCAATGTCACAACCTCTCTGATCTTGTGCTCAGCATGATTCTTTAATAGAA GTTTTATTTTTCGTGCACTCTGCTAATCATGTGGGTGAGCCAGTGGAACAGCGGGAGCCT GTGCTGGTTTGCAGATTGCCTCCTAATGACGCGGCTCAAAAGGAAACCAAGTGGTCAGGA GTTGTTTCTGACCCACTGATCTCTACTACCACAAGGAAAATAGTTTAGGAGAAACCAGCT TTTACTGTTTTTGAAAAATTACAGCTTCACCCTGTCAAGTTAACAAGGAATGCCTGTGCC AATAAAAGGTTTCTCCAACTTG (SEQ ID NO: 21)

[0339] As used herein, the term "CTSD" refers to the gene encoding cathepsin D. The terms "CTSD" and "cathepsin D" include wild-type forms of the CTSD gene, as well as variants of the wild-type CTSD (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type CTSD nucleic acid sequence (e.g., SEQ ID NO: 22, ENA Accession No. M11233). SEQ ID NO:22 is the wild-type gene sequence encoding the CTSD protein and is shown below. GGCTATAAGCGCACGGCCTCGGCGACCCTCTCCGACCCGGCCGCCGCCGCCATGCAGCCC TCCAGCCTTCTGCCGCTCGCCCTCTGCCTGCTGGCTGCACCCGCCTCCGCGCTCGTCAGG ATCCCGCTGCACAAGTTCACGTCCATCCGCCGGACCATGTCGGAGGTTGGGGGCTCTGTG GAGGACCTGATTGCCAAAGGCCCCGTCTCAAAGTACTCCCAGGCGGTGCCAGCCGTGACC GAGGGGCCCATTCCCGAGGTGCTCAAGAACTACATGGACGCCCAGTACTACGGGGAGATT GGCATCGGGACGCCCCCCCAGTGCTTCACAGTCGTCTTCGACACGGGCTCCTCCAACCTG TGGGTCCCCTCCATCCACTGCAAACTGCTGGACATCGCTTGCTGGATCCACCACAAGTAC AACAGCGACAAGTCCAGCACCTACGTGAAGAATGGTACCTCGTTTGACATCCACTATGGC TCGGGCAGCCTCTCCGGGTACCTGAGCCAGGACACTGTGTCGGTGCCCTGCCAGTCAGCG TCGTCAGCCTCTGCCCTGGGCGGTGTCAAAGTGGAGAGGCAGGTCTTTGGGGAGGCCACC AAGCAGCCAGGCATCACCTTCATCGCAGCCAAGTTCGATGGCATCCTGGGCATGGCCTAC CCCCGCATCTCCGTCAACAACGTGCTGCCCGTCTTCGACAACCTGATGCAGCAGAAGCTG GTGGACCAGAACATCTTCTCCTTCTACCTGAGCAGGGACCCAGATGCGCAGCCTGGGGGT GAGCTGATGCTGGGTGGCACAGACTCCAAGTATTACAAGGGTTCTCTGTCCTACCTGAAT GTCACCCGCAAGGCCTACTGGCAGGTCCACCTGGACCAGGTGGAGGTGGCCAGCGGGCTG ACCCTGTGCAAGGAGGGCTGTGAGGCCATTGTGGACACAGGCACTTCCCTCATGGTGGGC CCGGTGGATGAGGTGCGCGAGCTGCAGAAGGCCATCGGGGCCGTGCCGCTGATTCAGGGC GAGTACATGATCCCCTGTGAGAAGGTGTCCACCCTGCCCGCGATCACACTGAAGCTGGGA GGCAAAGGCTACAAGCTGTCCCCAGAGGACTACACGCTCAAGGTGTCGCAGGCCGGGAAG ACCCTCTGCCTGAGCGGCTTCATGGGCATGGACATCCCGCCACCCAGCGGGCCACTCTGG ATCCTGGGCGACGTCTTCATCGGCCGCTACTACACTGTGTTTGACCGTGACAACAACAGG GTGGGCTTCGCCGAGGCTGCCCGCCTCTAGTTCCCAAGGCGTCCGCGCGCCAGCACAGAA ACAGAGGAGAGTCCCAGAGCAGGAGGCCCCTGGCCCAGCGGCCCCTCCCACACACACCCA CACACTCGCCCGCCCACTGTCCTGGGCGCCCTGGAAGCCGGCGGCCCAAGCCCGACTTGC TGTTTTGTTCTGTGGTTTTCCCCTCCCTGGGTTCAGAAATGCTGCCTGCCTGTCTGTCTC TCCATCTGTTTGGTGGGGGTAGAGCTGATCCAGAGCACAGATCTGTTTCGTGCATTGGAA GACCCCACCCAAGCTTGGCAGCCGAGCTCGTGTATCCTGGGGCTCCCTTCATCTCCAGGG AGTCCCCTCCCCGGCCCTACCAGCGCCCGCTGGGCTGAGCCCCTACCCCACACCAGGCCG TCCTCCCGGGCCCTCCCTTGGAAACCTGCCCTGCCTGAGGGCCCCTCTGCCCAGCTTGGG CCCAGCTGGGCTCTGCCACCCTACCTGTTCAGTGTCCCGGGCCCGTTGAGGATGAGGCCG CTAGAGGCCTGAGGATGAGCTGGAAGGAGTGAGAGGGGACAAAACCCACCTTGTTGGAGC CTGCAGGGTGGTGCTGGGACTGAGCCAGTCCCAGGGGCATGTATTGGCCTGGAGGTGGGG TTGGGATTGGGGGCTGGTGCCAGCCTTCCTCTGCAGCTGACCTCTGTTGTCCTCCCCTTG GGCGGCTGAGAGCCCCAGCTGACATGGAAATACAGTTGTTGGCCTCCGGCCTCCCCTC (SEQ ID NO: 22)

[0340] As used herein, the term "CTSL" refers to the gene encoding cathepsin L1. The terms "CTSL" and "cathepsin L1" include wild-type forms of the CTSL gene, as well as variants of the wild-type CTSL (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type CTSL nucleic acid sequence (e.g., SEQ ID NO: 23, ENA Accession No. X12451). SEQ ID NO:23 is the wild-type gene sequence encoding the CTSL protein and is shown below. AGAACCGCGACCTCCGCAACCTTGAGCGGCATCCGTGGAGTGCGCCTGCAGCTACGACCG CAGCAGGAAAGCGCCGCCGGCCAGGCCCAGCTGTGGCCGGACAGGGACTGGAAGAGAGGA CGCGGTCGAGTAGGTGTGCACCAGCCCTGGCAACGAGAGCGTCTACCCCGAACTCTGCTG GCCTTGAGGTGGGGAAGCCGGGGGAGGGCAGTTGAGGACCCCGCGGAGGCGCGTGACTGGT TGAGCGGGCAGGCCAGCCTCCGAGCCGGGTGGACACAGGTTTTAAAACATGAATCCTACA CTCATCCTTGCTGCCTTTTGCCTGGGAATTGCCTCAGCTACTCTAACATTTGATCACAGT TTAGAGGCACAGTGGACCAAGTGGAAGGCGATGCACAACAGATTATACGGCATGAATGAA GAAGGATGGAGGAGAGCAGTGTGGGAGAAGAACATGAAGATGATTGAACTGCACAATCAG GAATACAGGGAAGGGAAACACAGCTTCACAATGGCCATGAACGCCTTTGGAGACATGACC AGTGAAGAATTCAGGCAGGTGATGAATGGCTTTCAAAACCGTAAGCCCAGGAAGGGGAAA GTGTTCCAGGAACCTCTGTTTTATGAGGCCCCCAGATCTGTGGATTGGAGAGAGAAAGGC TACGTGACTCCTGTGAAGAATCAGGGTCAGTGTGGTTCTTGTTGGGCTTTTAGTGCTACT GGTGCTCTTGAAGGACAGATGTTCCGGAAAACTGGGAGGCTTATCTCACTGAGTGAGCAG AATCTGGTAGACTGCTCTGGGCCTCAAGGCAATGAAGGCTGCAATGGTGGCCTAATGGAT TATGCTTTCCAGTATGTTCAGGATAATGGAGGCCTGGACTCTGAGGAATCCTATCCATAT GAGGCAACAGAAGAATCCTGTAAGTACAATCCCAAGTATTCTGTTGCTAATGACACCGGC TTTGTGGACATCCCTAAGCAGGAGAAGGCCCTGATGAAGGCAGTTGCAACTGTGGGGCCC ATTTCTGTTGCTATTGATGCAGGTCATGAGTCCTTCCTGTTCTATAAAGAAGGCATTTAT TTTGAGCCAGACTGTAGCAGTGAAGACATGGATCATGGTGTGCTGGTGGTTGGCTACGGA TTTGAAAGCACAGAATCAGATAACAATAAATATTGGCTGGTGAAGAACAGCTGGGGTGAA GAATGGGGCATGGGTGGCTACGTAAAGATGGCCAAAGACCGGAGAAACCATTGTGGAATT GCCTCAGCAGCCAGCTACCCCACTGTGTGAGCTGGTGGACGGTGATGAGGAAGGACTTGA CTGGGGATGGCGCATGCATGGGAGGAATTCATCTTCAGTCTACCAGCCCCCGCTGTGTCG GATACACACTCGAATCATTGAAGATCCGAGTGTGATTTGAATTCTGTGATATTTTCACAC TGGTAAATGTTACCTCTATTTTAATTACTGCTATAAATAGGTTTATATTATTGATTCACT TACTGACTTTGCATTTTCGTTTTTAAAAGGATGTATAAATTTTTACCTGTTTAAATAAAA TTTAATTTCAAATGT (SEQ ID NO:23)

[0341] As used herein, the term "CXCL10" refers to the gene encoding the CXC motif chemokine 10. The terms "CXCL10" and "CXC motif chemokine 10" include the wild-type form of the CXCL10 gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type CXCL10. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type CXCL10 nucleic acid sequence (e.g., SEQ ID NO: 24, ENA Accession No. X02530). SEQ ID NO: 24 is the wild-type gene sequence encoding the CXCL10 protein and is shown below. GAGACATTCCTCAATTGCTTAGACATATTCTGAGCCTACAGCAGAGGAACCTCCAGTCTC AGCACCATGAATCAAACTGCGATTCTGATTTGCTGCCTTATCTTTCTGACTCTAAGTGGC ATTCAAGGAGTACCTCTCTCTAGAACCGTACGCTGTACCTGCATCAGCATTAGTAATCAA CCTGTTAATCCAAGGTCTTTAGAAAAACTTGAAATTATTCCTGCAAGCCAATTTTGTCCA CGTGTTGAGATCATTGCTACAATGAAAAAGAAGGGTGAGAAGAGATGTCTGAATCCAGAA TCGAAGGCCATCAAGAATTTACTGAAAGCAGTTAGCAAGGAAATGTCTAAAAGATCTCCT TAAAACCAGAGGGGAGCAAAATCGATGCAGTGCTTCCAAGGATGGACCACACAGAGGCTG CCTCTCCCATCACTTCCCTACATGGAGTATATGTCAAGCCATAATTGTTCTTAGTTTGCA GTTACACTAAAAGGTGACCAATGATGGTCACCAAATCAGCTGCTACTACTCCTGTAGGAA GGTTAATGTTCATCATCCTAAGCTATTCAGTAATAACTCTACCCTGGCACTATAATGTAA GCTCTACTGAGGTGCTATGTTCTTAGTGGATGTTCTGACCCTGCTTCAAATATTTCCCTC ACCTTTCCCATCTTCCAAGGGTACTAAGGAATCTTTCTGCTTTGGGGTTTATCAGAATTC TCAGAATCTCAAATAACTAAAAGGTATGCAATCAAATCTGCTTTTTAAAGAATGCTCTTT ACTTCATGGACTTCCACTGCCATCCTCCCAAGGGGCCCAAATTCTTTCAGTGGCTACCTA CATACAATTCCAAACACATACAGGAAGGTAGAAATATCTGAAAATGTATGTGTAAGTATT CTTATTTAATGAAAGACTGTACAAAGTATAAGTCTTAGATGTATATATTTCCTATATTGT TTTCAGTGTACATGGAATAACATGTAATTAAGTACTATGTATCAATGAGTAACAGGAAAA TTTTAAAAATACAGATAGATATATGCTCTGCATGTTACATAAGATAAATGTGCTGAATGG TTTTCAAATAAAAATGAGGTACTCTCCTGGAAATATTAAGAAAGACTATCTAAATGTTGA AAGATCAAAAGGTTAATAAAGTAATTATAACT (SEQ ID NO:24)

[0342] As used herein, the term "CXCL13" refers to the gene encoding the C-X-C motif chemokine 13. The terms "CXCL13" and "C-X-C motif chemokine 13" include wild-type forms of the CXCL13 gene, as well as variants of the wild-type CXCL13 (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type CXCL13 nucleic acid sequence (e.g., SEQ ID NO: 25, ENA Accession No. AF044197). SEQ ID NO: 25 is the wild-type gene sequence encoding the CXCL13 protein and is shown below. TTCGGCACTTGGGAGAAGATGTTTGAAAAAAACTGACTCTGCTAATGAGCCTGGACTCAGA GCTCAAGTCTGAACTCTACCTCCAGACAGAATGAAGTTCATCTCGACATCTCTGCTTCTC ATGCTGCTGGTCAGCAGCCTCTCTCCAGTCCAAGGTGTTCTGGAGGTCTATTACACAAGC TTGAGGTGTAGATGTGTCCAAGAGAGCTCAGTCTTTATCCCTAGACGCTTCATTGATCGA ATTCAAATCTTGCCCCGTGGGAATGGTTGTCCAAGAAAAGAAATCATAGTCTGGAAGAAG AACAAGTCAATTGTGTGTGTGGACCCTCAAGCTGAATGGATACAAAGAATGATGGAAGTA TTGAGAAAAGAAGTTCTTCAACTCTACCAGTTCCAGTGTTTAAGAGAAAGATTCCCTGA TGCTGATATTTCCACTAAGAACACCTGCATTCTTCCCTTATCCCTGCTCTGGATTTTAGT TTTGTGCTTAGTTAAATCTTTTCCAGGGAGAAAGAACTTCCCCATACAAATAAGGCATGA GGACTATGTGAAAAATAACCTTGCAGGAGCTGATGGGGCAAACTCAAGCTTCTTCACTCA CAGCACCCCTATATACACTTGGAGTTTGCATTCTTATTCATCAGGGAGGAAAGTTTCTTTG AAAATAGTTATTCAGTTATAAGTAATACAGGATTATTTTGATTATATACTTGTTGTTTAA TGTTTAAAATTTCTTAGAAAACAATGGAATGAGAATTTAAGCCTCAAATTTGAACATGTG GCTTGAATTAAGAAGAAAATTATGGCATATATTAAAAGCAGGCTTCTATGAAAGACTCAA AAAGCTGCCTGGGAGGCAGATGGAACTTGAGCCTGTCAAGAGGCAAAGGAATCCATGTAG TAGATATCCTCTGCTTAAAAACTCACTACGGAGGAGAATTAAGTCCTACTTTTAAAGAAT TTCTTTATAAAATTTACTGTCTAAGATTAATAGCATTCGAAGATCCCCAGACTTCATAGA ATACTCAGGGAAAGCATTTAAAGGGTGATGTACACATGTATCCTTTCACACATTTGCCTT GACAAACTTCTTTCACTCACATCTTTTTTCACTGACTTTTTTTGTGGGGGCGGGGCCGGGG GGACTCTGGTATCTAATTCTTTAATGATTCCTATAAATCTAATGACATTCAATAAAGTTG AGCAAACATTTTTACTT (SEQ ID NO:25)

[0343] As used herein, the term "DSG2" refers to the gene encoding Desmoglein 2. The terms "DSG2" and "Desmoglein 2" include wild-type forms of the DSG2 gene, as well as mutant forms of the wild-type DSG2 (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type DSG2 nucleic acid sequence (e.g., SEQ ID NO: 26, NCBI Reference Sequence: NM_001943.4). SEQ ID NO: 26 is the wild-type gene sequence encoding the DSG2 protein and is shown below. ATGTTTCAAAATATATGTGCATTATCAGTAATAATTTGTATAAATATTTCCCACAACAATTTTCATAATTTTCAAAGACTAATTTCTTGACTGAAGATATTTTGCTAGGGAAGTGAAACTTTAAAATTTTGTAGATTTTAAAAAATATTGTTGAATGGTGTCATGCAAAGGATTTATATAGTGTGCTCCCACTAACTGTACAGATCAGGACACATATTTTTAGACATCTAAGTCTGTAGCTTAAATGGAGGTTACTCTTCCATCATCTAGAATTGTTTACTTAGTAATTGTTGTTTCTTTTATTATTATAGACTTACTATCAGTTTTATTTTGCCAAGTATGCAACAGGTATATCACTAGTATATGAAAATGTAAATATCACTTGTGTACTCAAACAAAAGTTGGTCTTAAGCTTCCACCTTGAGCAGCCTTGGAAACCTAACCTGCCTCTTTTAGCATAATCACATTTTCTAAATGATTTTCTTTGTTCCTGAAAAAGTGATTTGTATTAGTTTTACATTTGTTTTTTGGAAGATTATATTTGTATATGTATCATCATAAAATATTTAAATAAAAAGTATCTTTAGAGTGACCCTTTCCCCATAGATTTTTATTTCTCTATTATATTTTACAAGGAATATAACTCAGTTTGTTAGGGAGAGTGCCTTAAAGGCAGGTGTTTCTTGGACTTTGTTATTTAATTAGATCTGCTTGCAATAAAAAAAGTTGTCGGTTATCTAAAATTCAAAAAAAAAAAAAAAAAA (SEQ ID NO: 26)

[0344] As used herein, the term "ECHDC3" refers to a gene encoding enoyl-CoA hydratase domain-containing 3. The terms "ECHDC" and "enoyl-CoA hydratase domain-containing 3" include wild-type forms of the ECHDC gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type ECHDC. An example of such a variant is a nucleic acid having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type ECHDC nucleic acid sequence (e.g., SEQ ID NO: 27, NCBI Reference Sequence: NM_024693.4). SEQ ID NO: 27 is the wild-type gene sequence encoding the ECHDC protein and is shown below. (SEQ ID NO:27)

[0345] As used herein, the term "EPHA1" refers to the gene encoding Ephrin type-A receptor 1. The terms "EPHA1" and "Ephrin type-A receptor 1" include wild-type forms of the EPHA1 gene, as well as variants of the wild-type EPHA1 (e.g., splice variants and polymorphisms). An example of such a variant is a nucleic acid having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type EPHA1 nucleic acid sequence (e.g., SEQ ID NO: 28, ENA Accession No. M18391). SEQ ID NO: 28 is the wild-type gene sequence encoding the EPHA1 protein and is shown below. GCCCCCGCCCGGCCCGCCCCGCTCTCCTAGTCCCTTGCAACCTGGCGCTGCATCCGGGCC ACTGTCCCAGGTCCCAGGTCCCGGCCCGGAGCTATGGAGCGGCGCTGGCCCCTGGGGCTA GGGCTGGTGCTGCTGCTCTGCGCCCCGCTGCCCCCGGGGGCGCGCGCCAAGGAAGTTACT CTGATGGACACAAGCAAGGCACAGGGAGAGCTGGGCTGGCTGCTGGATCCCCCAAAAGAT GGGTGGAGTGAACAGCAACAGATACTGAATGGGACACCCCTCTACATGTACCAGGACTGC CCAATGCAAGGACGCAGAGACACTGACCACTGGCTTCGCTCCAATTGGATCTACCGCGGG GAGGAGGCTTCCCGCGTCCACGTGGAGCTGCAGTTCACCGTGCGGGACTGCAAGAGTTTC CCTGGGGGAGCCGGGCCTCTGGGCTGCAAGGAGACCTTCAACCTTCTGTACATGGAGAGT GACCAGGATGTGGGCATTCAGCTCCGACGGCCCTTGTTCCAGAAGGTAACCACGGTGGCT GCAGACCAGAGCTTCACCATTCGAGACCTTGCGTCTGGCTCCGTGAAGCTGAATGTGGAG CGCTGCTCTCTGGGCCGCCTGACCCGCCGTGGCCTCTACCTCGCTTTCCACAACCCGGGT GCCTGTGTGGCCCTGGTGTCTGTCCGGGTCTTCTACCAGCGCTGTCCTGAGACCCTGAAT GGCTTGGCCCAATTCCCAGACACTCTGCCTGGCCCCGCTGGGTTGGTGGAAGTGGCGGGC ACCTGCTTGCCCCACGCGCGGGCCAGCCCCAGGCCCTCAGGTGCACCCCGCATGCACTGC AGCCCTGATGGCGAGTGGCTGGTGCCTGTAGGACGGTGCCACTGTGAGCCTGGCTATGAG GAAGGTGGCAGTGGCGAAGCATGTGTTGCCTGCCCTAGCGGCTCCTACCGGATGGACATG GACACACCCCATTGTCTCACGTGCCCCCAGCAGAGCACTGCTGAGTCTGAGGGGGCCACC ATCTGTACCTGTGAGAGCGGCCATTACAGAGCTCCCGGGGAGGGCCCCCAGGTGGCATGC ACAGGTCCCCCCTCGGCCCCCCGAAACCTGAGCTTCTCTGCCTCAGGGACTCAGCTCTCC CTGCGTTGGGAACCCCCAGCAGATACGGGGGGACGCCAGGATGTCAGATACAGTGTGAGG TGTTCCCAGTGTCAGGGCACAGCACAGGACGGGGGGCCCTGCCAGCCCTGTGGGGTGGGC GTGCACTTCTCGCCGGGGGCCCGGGCGCTCACCACACCTGCAGTGCATGTCAATGGCCTT GAACCTTATGCCAACTACACCTTTAATGTGGAAGCCCAAAATGGAGTGTCAGGGCTGGGC AGCTCTGGCCATGCCAGCACCTCAGTCAGCATCAGCATGGGGCATGCAGAGTCACTGTCA GGCCTGTCTCTGAGACTGGTGAAGAAAGAACCGAGGAACTAGAGCTGACCTGGGCGGGG TCCCGGCCCCGAAGCCCTGGGGCGAACCTGACCTATGAGCTGCACGTGCTGAACCAGGAT GAAGAACGGTACCAGATGGTTCTAGAACCAGGGTCTTGCTGACAGAGCTGCAGCCTGAC ACCACATACATCGTCAGAGTCGAATGCTGACCCCCACTGGGTCCTGGCCTTTCTCCCCT GATCATGAGTTTCGGACCAGCCCACCAGTGTCCAGGGGCCTGACTGGAGGAGAGATTGTA GCCGTCATCTTTGGGCTGCTGCTTGGTGCAGCCTTGCTGCTTGGGATTCTCGTTTTCCGG TCCAGGAGAGCCCAGCGGCAGAGGCAGCAGAGGCACGTGACCGCGCCACCGATGTGGATC GAGAGGACAAGCTGTGCTGAAGCCTTATGTGGTACCTCCAGGCATACGAGGACCCTGCAC AGGGAGCCTTGGACTTTACCCGGAGGCTGGCTAATTTTCCTTCCCGGGAGCTTGATCCA GCGTGGCTGATGGTGGACACTGTCATAGGAGAAGGAGAGTTTGGGGAAGTGTATCGAGGG ACCCTCAGGCTCCCCAGCCAGGACTGCAAGACTGTGGCCATTAAGACCTTAAAAGACACA TCCCCAGGTGGCCAGTGGTGGAACTTCCTTCGAGAGGCAACTATCATGGGCCAGTTTAGC CACCCGCATATTCTGCATCTGGAAGGCGTCGTCACAAAGCGAAAGCCGATCATGATCATC ACAGAATTTATGGAGAATGCAGCCCTGGATGCCTTCCTGAGGGAGCGGGAGGACCAGCTG GTCCCTGGGCAGCTAGTGGCCATGCTGCAGGGCATAGCATCTGGCATGAACTACCTCAGT AATCACAATTATGTCCACCGGGACCTGGCTGCCAGAAACATCTTGGTGAATCAAAACCTG TGCTGCAAGGTGTCTGACTTTGGCCTGACTCGCCTCCTGGATGACTTTGATGGCACATAC GAAACCCAGGGAGGAAAGATCCCTATCCGTTGGACAGCCCCTGAAGCCATTGCCCATCGG ATCTTCACCACAGCCAGCGATGTGTGGAGCTTTGGGATTGTGATGTGGGAGGTGCTGAGC TTTGGGGACAAGCCTTATGGGGAGATGAGCAATCAGGAGGTTATGAAGAGCATTGAGGAT GGGTACCGGTTGCCCCCTCCTGTGGACTGCCCTGCCCCTCTGTATGAGCTCATGAAGAAC TGCTGGGCATATGACCGTGCCCGCCGGCCACACTTCCAGAAGCTTCAGGCACATCTGGAG CAACTGCTTGCCAACCCCCACTCCCTGCGGACCATTGCCAACTTTGACCCCAGGGTGACT CTTCGCCTGCCCAGCCTGAGTGGCTCAGATGGGATCCCGTATCGAACCGTCTCTGAGTGG CTCGAGTCCATACGCATGAAACGCTACATCCTGCACTTCCACTCGGCTGGGCTGGACACC ATGGAGTGTGTGCTGGAGCTGACCGCTGAGGACCTGACGCAGATGGGAATCACACTGCCC GGGCACCAGAAGCGCATTCTTTGCAGTATTCAGGGATTCAAGGACTGATCCCTCCTCTCA CCCCATGCCCAATCAGGGTGCAAGGAGCAAGGACGGGGCCAAGGTCGCTCATGGTCACTC CCTGCGCCCCTTCCCACAACCTGCCAGACTAGGCTATCGGTGCTGCTTCTGCCCGCTTTA AGGAGAACCCTGCTCTGCACCCCAGAAAACCTCTTTGTTTTAAAAGGGAGGTGGGGGTAG AAGTAAAAGGATGATCATGGGAGGGAGCTCAGGGGTTAATATATATACATACATACACAT ATATATATTGTTGTAAATAAACAGGAAATGATTTTCTGCCTCCATCCCACCCATCAGGGC TGCAGGCACT (SEQ ID NO: 28)

[0346] As used herein, the term "FABP5" refers to a gene encoding fatty acid binding protein 5. The terms "FABP5" and "fatty acid binding protein 5" include wild-type forms of the FABP5 gene, as well as mutants (e.g., splice variants and polymorphisms) of the wild-type FABP5. Examples of such mutants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type FABP5 nucleic acid sequence (e.g., SEQ ID NO: 29, ENA Accession No. M94856). SEQ ID NO:29 is the wild-type gene sequence encoding the FABP5 protein and is shown below. ACCGCCGACGCAGACCCCTCTCTGCACGCCAGCCCGCCCGCACCCACCATGGCCACAGTT CAGCAGCTGGAAGGAAGATGGCGCCTGGTGGACAGCAAAGGCTTTGATGAATACATGAAG GAGCTAGGAGTGGGAATAGCTTTGCGAAAAAATGGGCGCAATGGCCAAGCCAGATTGTATC ATCACTTGTGATGGTAAAAACCTCACCATAAAAACTGAGAGCACTTTGAAAACAACACAG TTTTCTTGTACCCTGGGAGAGAAGTTTGAAGAAACCACAGCTGATGGCAGAAAAACTCAG ACTGTCTGCAACTTTACAGATGGTGCATTGGTTCAGCATCAGGAGTGGGATGGGAAGGAA AGCACAATAACAAGAAAATTGAAAGATGGGAAATTTAGTGGTGGAGTGTGTCATGAACAAT GTCACCTGTACTCGGATCTATGAAAAAGTAGAATAAAAATTCCATCATCACTTTGGACAG GAGTTAATTAAGAGAATGACCAAGCTCAGTTCAATGAGCAAATCTCCATACTGTTTCTTT CTTTTTTTTTTCATTACTGTGTTCAATTATCTTTATCATAAACATTTTACATGCAGCTAT TTCAAAGTGTGTTGGATTAATTAGGATCATCCCTTTGGTTAATAAATAAATGTGTTTGTGCT (SEQ ID NO:29)

[0347] As used herein, the term "FERMT2" refers to the gene encoding fermitin family homolog 2. The terms "FERMT2" and "fermitin family homolog 2" include wild-type forms of the FERMT2 gene, as well as mutant forms of the wild-type FERMT2 (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type FERMT2 nucleic acid sequence (e.g., SEQ ID NO: 30, ENA Accession No. Z24725). SEQ ID NO: 30 is the wild-type gene sequence encoding the FERMT2 protein and is shown below. CAAAAAGTGTGTGGAAAGGTGGATTGAGGGAGCGGGACCCCCGCGGGACCCGAGGGGGCG GCAGGCGGGAACGGGAGTCAGCCCGCGCTGTGTCTCGGGGCCGGCCGGCAGGAAGGAG CCATGGCTCTGGACGGGATAAGGATGCCAGATGGCTGCTACGCGGACGGGACGTGGGAAC TGAGTGTCCATGTGACGGACCTGAACCGCGATATCACCCTGAGAGTGACCGGCGAGGTGC ACATTGGAGGCGTGATGCTTAAGCTGGTGGAGAAACTCGATGTAAAAAAAGATTGGTCTG ACCATGCTCTCTGGTGGGAAGAAGAGAACTTGGCTCTCTGAAGACACATTGGACCTTAG ATAAGTATGGTATTCAGGCAGATGCTAAGCTTCAGTTCACCCCTCAGCACAAACTGCTCC GCCTGCAGCTTCCCAACATGAAGTATGTGAAGGTGAAAGTGAATTTCTCTGATAGAGTCT TCAAAGCTGTTCTGACATCTGTAAGACTTTTAATATCAGACACCCCGAAGAACTTTCTC TCTTAAAGAAACCCAGAGATCCAACAAAGAAAGAAGAAGAAGCTAGATGACCAGTCTG AAGATGAGGCACTTGAATTAGAGGGGCCTCTTATCACTCCTGGATCAGGAAGTATATATT CAAGCCCAGGACTGTATAGTAAAACAATGACCCCCACTTATGATGCTCATGATGGAAGCC CCTTGTCACCAACTTCTGCTTGGTTTGGTGACAGTGCTTTGTCAGAAGGCAATCCTGGTA TACTTGCTGTCAGTCAACCAATCACGTCACCAGAAATCTTGGCAAAAATGTTCAAGCCTC AAGCTCTTCTTGATAAAGCAAATTCAACCAAGGATGGCTTGATTCCTCAAGATCTCTCA TGGAACAAGATGTGAAGGAAAATGAGGCCTTGCTGCTCCGATTCAAGTATTACAGCTTTT TTGATTTGAATCCAAAGTATGATGCAATCAGAATCAATCAGCTTTATGAGCAGGCCAAAT GGGCCATTCTCCTGGAAGAGATTGAATGCACAGAAGAAGAAATGATGATGTTTGCAGCCC TGCAGTATCATATCAATAAGCTGTCAATCATGACATCAGAGAATCATTTGAACAACAGTG ACAAAGAAGTTGATGAAGTTGATGCTGCCCTTTCAGACCTGGAGATTACTCTGGAAGGGG GTAAAACGTCAACAATTTTGGGTGACATTACTTCCATTCCTGAACTTGCTGACTACATTA AAGTTTTCAAGCCAAAAAAGCTGACTCTGAAAGGTTACAAACAATATTGGTGCACCTTCA AAGACACATCCATTTCTTGTTATAAGAGCAAAGAAGAATCCAGTGGCACACCAGCTCATC AGATGAACCTCAGGGGATGTGAAGTTACCCCAGATGTAAACATTTCAGGCCAAAAATTTA ACATTAAACTCCTGATTCCAGTTGCAGAAGGCATGAATGAAATCTGGCTTCGTTGTGACA ATGAAAAACAGTATGCACACTGGATGGCAGCCTGCAGATTAGCCTCCAAAGGCAAGACCA TGGCGGACAGTTCTTACAACTTAGAAGTTCAGAATATTCTTTCCTTTCTGAAGATGCAGC ATTTAAACCCAGATCCTCAGTTAATACCAGAGCAGATCACGACTGATATAACTCCTGAAT GTTTGGTGTCTCCCCGCTATCTAAAAAAGTATAAGAACAAGCAGATAACAGCGAGAATCT TGGAGGCCCATCAGAATGTAGCTCAGATGAGTCTAATTGAAGCCAAGATGAGATTTATTC AAGCTTGGCAGTCACTACCTGAATTTGGCATCACTCACTTCATTGCAAGGTTCCAAGGGG GCAAAAAAGAAGAACTTATTGGAATTGCATACAACAGACTGATTCGGATGGATGCCAGCA CTGGAGATGCAATTAAAACATGGCGTTTCAGCAACATGAAACAGTGGAATGTCAACTGGG AAATCAAAATGGTCACCGTAGAGTTTGCAGATGAAGTACGATTGTCCTTCATTTGTACTG AAGTAGATTGCAAAGTGGTTCATGAATTCATTGGTGGCTACATATTTCTCTCAACACGTG CAAAAGACCAAAACGAGAGTTTAGATGAAGAGATGTTCTACAAACTTACCAGTGGTTGGG TGTGAATAGAAATACTGTTTAATGAAACTCCACGGCCATAACAATATTTAACTTTAAAAG CTGTTTGTTATATGCTGCTTAATAAAGTAAGCTTGAAATTTATCATTTTATCATGAAAAC TTCTTTGCCTTACCAGACCAGTTAATATGTGCACTAAACAAGCACGACTATTAATCTATC ATGTTATGATATAATAAACTTGAATTTGGCACACATTCCTTAGGGCCATGAATTGAAAAC TGAAATAGTGGGCAAATCAGGAACAAACCATCACTGATTTACTGATTTAAGCTAGCCAAA CTGTAAGAAACAAGCCATCTATTTTAAAGCTATCCAGGGCTTAACCTATATGAACTCTAT TTATCATGTCTAATGCATGTGATTTAATGTATGTTTAATTTGATATCATGTTTTAAAATA TCCTACTTCTGGTAGCCATTTAATTCCTCCCCCTACCCCCAAATAAATCAGGCATGCAGG AGGCCTGATATTTAGTAATGTCATTGTGTTTGACCTTGAAGGAAAATGCTATTAGTCCGT CGTGCTTNATTTGTTTTTGTCCTTGAATAAGCATGTTATGTATATNGTCTCGTGTTTTTA TTTTTACACCATATTGTATTACACTTTTAGTATTCACCAGCATAANCACTGTCTGCCTAA AATATGCAACTCTTTGCATTACAATATGAAGTAAAGTTCTATGAAGTATGCATTTTGTGT AACTAATGTAAAAACACAAATTTTATAAAATTGTACAGTTTTTTAAAAACTACTCACAAC TAGCAGATGGCTTAAATGTAGCAATCTCTGCGTTAATTAAATGCCTTTAAGAGATATAAT TAACGTGCAGTTTTAATATCTACTAAATTAAGAATGACTTCATTATGATCATGATTTGCC ACAATGTCCTTAACTCTAATGCCTGGACTGGCCATGTTCTAGTCTGTTGCGCTGTTACAA TCTGTATTGGTGCTAGTCAGAAAATTCCTAGCTCACATAGCCCAAAAGGGTGCGAGGGAG AGGTGGATTACCAGTATTGTTCAATAATCCATGGTTCAAAGACTGTATAAATGCATTTTA TTTTAAATAAAAGCAAAACTTTTATTTAAA (SEQ ID NO: 30)

[0348] As used herein, the term "FTH1" refers to a gene encoding a ferritin heavy chain. The terms "FTH1" and "ferritin heavy chain" include wild-type forms of the FTH1 gene, as well as variants of wild-type FTH1 (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type FTH1 nucleic acid sequence (e.g., SEQ ID NO: 31, ENA Accession No. X00318). SEQ ID NO:31 is the wild-type gene sequence encoding the FTH1 protein and is shown below. CACCGCACCCTCGGACTGCCCCAAGGCCCCCGCCGCCGCTCCAGCGCCGCGCAGCCACCGCCGCCGCCGCCGCCTCTCCTTAGTCGCCGCCATGACGACCGCGTCCACCTCGCAGGTGCGCCAGAACTACCACCAGGACTCAGAGGCCGCCATCAACCGCCAGATCAACCTGGAGCTCTACGCCTCCTACGTTTACCTGTCCATGTCTTACTACTTTGACCGCGATGATGTGGCTTTGAAGAACTTTGCCAAATACTTTCTTCACCAATCTCATGAGGAGAGGGAACATGCTGAGAAACTGATGAAGCTGCAGAACCAACGAGGTGGCCGAATCTTCCTTCAGGATATCAAGAAACCAGACTGTGATGACTGGGAGAGCGGGCTGAATGCAATGGAGTGTGCATTACATTTGGAAAAAAATGTGAATCAGTCACTACTGGAACTGCACAAACTGGCCACTGACAAAAATGACCCCCATTTGTGTGACTTCATTGAGACACATTACCTGAATGAGCAGGTGAAAGCCATCAAAGAATTGGGTGACCACGTGACCAACTTGCGCAAGATGGGAGCGCCCGAATCTGGCTTGGCGGAATATCTCTTTGACAAGCACACCTGGGAGACAGTGATAATGAAAGCTAAGCCTCGGGCTAATTTCCCATAGCCGTGGGGTGACTTCCTGGTCACCAAGGCAGTGCATGCATGTTGGGGTTTCCTTTACCTTTTCTATAAGTTGTACCAAAACATCCACTTAAGTTCTTTGATTTGTACCATTCCTTCAAATAAAGAAATTTGGTACCC (SEQ ID NO: 31)

[0349] As used herein, the term "GNAS" refers to the gene encoding the guanine nucleotide-binding protein G(s) subunit alpha isoform XLas. The terms "GNAS" and "guanine nucleotide-binding protein G(s) subunit alpha isoform XLas" include wild-type forms of the GNAS gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type GNAS. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type GNAS nucleic acid sequence (e.g., SEQ ID NO: 32, ENA Accession No. X04408). SEQ ID NO: 32 is the wild-type gene sequence encoding the GNAS protein and is shown below. GCGGGCGTGCTGCCGCCGCTGCCGCCGCCGCCGCAGCCCGGCCGCGCCCCGCCGCCGCCG CCGCCGCCATGGGCTGCCTCGGGAACAGTAAGACCGAGGACCAGCGCAACGAGGAGAAGG CGCAGCGTGAGGCCAACAAAAAGATCGAGAAGCAGCTGCAGAAGGACAAGCAGGTCTACC GGGCCACGCACCGCCTGCTGCTGCTGGGGTGCTGGAGAATCTGGTAAAAGCACCATTGTGA AGCAGATGAGGATCCTGCATGTTAATGGGTTTAATGGAGAGGGCGGCGAAGAGGACCCGC AGGCTGCAAGGAGCAACAGCGATGGTGAGAAGGCAACCAAAGTGCAGGACATCAAAAACA ACCTGAAAGAGGCGATTGAAACCATTGTGGCCGCCATGAGCAACCTGGTGCCCCCCGTGG AGCTGGCCAACCCCGAGAACCAGTTCAGAGTGGACTACATCCTGAGTGTGATGAACGTGC CTGACTTTGACTTCCCTCCCGAATTCTATGAGCATGCCAAGGCTCTGTGGGAGGATGAAG GAGTGCGTGCCTGCTACGAACGCTCCAACGAGTACCAGCTGATTGACTGTGCCCAGTACT TCCTGGACAAGATCGACGTGATCAAGCAGGCTGACTATGTGCCGAGCGATCAGGACCTGC TTCGCTGCCGTGTCCTGACTTCTGGAATCTTTGAGACCAAGTTCCAGGTGGACAAAGTCA ACTTCCACATGTTTGACGTGGGTGGCCAGCGCGATGAACGCCGCAAGTGGATCCAGTGCT TCAACGATGTGACTGCCATCATCTTCGTGGTGGCCAGCAGCAGCTACAACATGGTCATCC GGGAGGACAACCAGACCAACCGCCTGCAGGAGGCTCTGAACCTCTTCAAGAGCATCTGGA ACAACAGATGGCTGCGCACCATCTCTGTGATCCTGTTCCTCAACAAGCAAGATCTGCTCG CTGAGAAAGTCCTTGCTGGGAAATCGAAGATTGAGGACTACTTTCCAGAATTTGCTCGCT ACACTACTCCTGAGGATGCTACTCCCGAGCCCGGAGAGGACCCACGCGTGACCCGGGCCA AGTACTTCATTCGAGATGAGTTTCTGAGGATCAGCACTGCCAGTGGAGATGGGCGTCACT ACTGCTACCCTCATTTCACCTGCGCTGTGGACACTGAGAACATCCGCCGTGTGTTCAACG ACTGCCGTGACATCATTCAGCGCATGCACCTTCGTCAGTACGAGCTGCTCTAAGAAGGGA ACCCCCAAATTTAATTAAAGCCTTAAGCACAATTAATTAAAAGTGAAACGTAATTGTACA AGCAGTTAATCACCCACCATAGGGCATGATTAACAAAGCAACCTTTCCCTTCCCCCGAGT GATTTTGCGAAACCCCCTTTTCCCTTCAGCTTGCTTAGATGTTCCAAATTTAGAAAGCTT AAGCGGCCTACAGAAAAAGGAAAAAAGGCCACAAAAGTTCCCTCTCACTTTCAGTAAAA ATAAATAAAACAGCAGCAGCAAACAAATAAAATGAAATAAAAGAAACAAATGAAATAAAT ATTGTGTTGTGCAGCATTAAAAAAAAATCAAAATAAAAATTAAATGTGAGCAAAG (SEQ ID NO:32)

[0350] As used herein, the term "GRN" refers to a gene encoding progranulin. The terms "GRN" and "progranulin" include wild-type forms of the GRN gene, as well as variants of wild-type GRN (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type GRN nucleic acid sequence (e.g., SEQ ID NO: 33, ENA Accession No. X62320). SEQ ID NO:33 is the wild-type gene sequence encoding the GRN protein and is shown below. GCTGCTGCCCAAGGACCGCGGAGTCGGACGCAGGCAGACCATGTGGACCCTGGTGAGCTG GGTGGCCTTAACAGCAGGGCTGGTGGCTGGAACGCGGTGCCCAGATGGTCAGTTCTGCCC TGTGGCCTGCTGCCTGGACCCCGGAGGAGCCAGCTACAGCTGCTGCCGTCCCCTTCTGGA CAAATGGCCCACAACACTGAGCAGGCATCTGGGTGGCCCCTGCCAGGTTGATGCCCACTG CTCTGCCGGCCACTCCTGCATCTTTACCGTCTCAGGGACTTCCAGTTGCTGCCCCTTCCC AGAGGCCGTGGCATGCGGGGATGGCCATCACTGCTGCCCACGGGGCTTCCACTGCAGTGC AGACGGGCGATCCTGCTTCCAAAGATCAGGTAACAACTCCGTGGGTGCCATCCAGTGCCC TGATAGTCAGTTCGAATGCCCGGACTTCTCCACGTGCTGTGTTATGGTCGATGGCTCCTG GGGGTGCTGCCCCATGCCCCAGGCTTCCTGCTGTGAAGACAGGGTGCACTGCTGTCCGCA CGGTGCCTTCTGCGACCTGGTTCACACCCGCTGCATCACACCCACGGGCACCCACCCCCT GGCAAAGAAGCTCCCTGCCCAGAGGACTAACAGGGCAGTGGCCTTGTCCAGCTCGGTCAT GTGTCCGGACGCACGGTCCCGGTGCCCTGATGGTTCTACCTGCTGTGAGCTGCCCAGTGG GAAGTATGGCTGCTGCCCAATGCCCAACGCCACCTGCTGCTCCGATCACCTGCACTGCTG CCCCCAAGACACTGTGTGTGACCTGATCCAGAGTAAGTGCCTCTCCAAGGAGAACGCTAC CACGGACCTCCTCACTAAGCTGCCTGCGCACACAGTGGGGGATGTGAAATGTGACATGGA GGTGAGCTGCCCAGATGGCTATACCTGCTGCCGTCTACAGTCGGGGGCCTGGGGCTGCTG CCCTTTTACCCAGGCTGTGTGCTGTGAGGACCACATACACTGCTGTCCCGCGGGGTTTAC GTGTGACACGCAGAAGGGTACCTGTGAACAGGGGCCCCACCAGGTGCCCTGGATGGAGAA GGCCCCAGCTCACCTCAGCCTGCCAGACCCACAAGCCTTGAAGAGAGATGTCCCCTGTGA TAATGTCAGCAGCTGTCCCTCCTCCGATACCTGCTGCCAACTCACGTCTGGGGAGTGGGG CTGCTGTCCAATCCCAGAGGCTGTCTGCTGCTCGGACCACCAGCACTGCTGCCCCCAGGG CTACACGTGTGTAGCTGAGGGGCAGTGTCAGCGAGGAAGCGAGATCGTGGCTGGACTGGA GAAGATGCCTGCCCGCCGGGCTTCCTTATCCCACCCCAGAGACATCGGCTGTGACCAGCA CACCAGCTGCCCGGTGGGGCAGACCTGCTGCCCGAGCCTGGGTGGGAGCTGGGCCTGCTG CCAGTTGCCCCATGCTGTGTGCTGCGAGGATCGCCAGCACTGCTGCCCGGCTGGCTACAC CTGCAACGTGAAGGCTCGATCCTGCGAGAAGGAAGTGGTCTCTGCCCAGCCTGCCACCTT CCTGGCCCGTAGCCCTCACGTGGGTGTGAAGGACGTGGAGTGTGGGGAAGGACACTTCTG CCATGATAACCAGACCTGCTGCCGAGACAACCGACAGGGCTGGGCCTGCTGTCCCTACCG CCAGGGCGTCTGTTGTGCTGATCGGCGCCACTGCTGTCCTGCTGGCTTCCGCTGCGCAGC CAGGGGTACCAAGTGTTTGCGCAGGGAGGCCCCGCGCTGGGACGCCCCTTTGAGGGACCC AGCCTTGAGACAGCTGCTGTGAGGGACAGTACTGAAGACTCTGCAGCCCTCGGGACCCCA CTCGGAGGGTGCCCTCTGCTCAGGCCTCCCTAGCACCTCCCCCTAACCAAATTCTCCCTG GACCCCATTCTGAGCTCCCCATCACCATGGGAGGTGGGGCCTCAATCTAAGGCCTTCCCT GTCAGAAGGGGGTTGTGGCAAAAGCCACATTACAAGCTGCCATCCCCTCCCCGTTTCAGT GGACCCTGTGGCCAGGTGCTTTTCCCTATCCACAGGGGTGTTTGTGTGTGTGCGCGTGTG CGTTTCAATAAAGTTTGTACACTTTCAAAAAAAAAAAAAAAAAAAAAAAAAA (SEQ ID NO: 33)

[0351] As used herein, the term "HBEGF" refers to the gene encoding a heparin-binding EGF-like growth factor. The terms "HBEGF" and "heparin-binding EGF-like growth factor" include wild-type forms of the HBEGF gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type HBEGF. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type HBEGF nucleic acid sequence (e.g., SEQ ID NO: 34, NCBI Reference Sequence: NM_001945.2). SEQ ID NO: 34 is the wild-type gene sequence encoding the HBEGF protein and is shown below. (SEQ ID NO:34)

[0352] As used herein, the term "HLA-DRB1" refers to the gene encoding the HLA class II histocompatibility antigen, DRB1 beta chain. The terms "HLA-DRB1" and "HLA class II histocompatibility antigen, DRB1 beta chain" include the wild-type form of the HLA-DRB1 gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type HLA-DRB1. An example of such a variant is a nucleic acid having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type HLA-DRB1 nucleic acid sequence (e.g., SEQ ID NO: 35, ENA Accession No. X00699). SEQ ID NO: 35 is the wild-type gene sequence encoding the HLA-DRB1 protein and is shown below. CTGCTCTGGCCCCTGGTCCTGTCCTGTTCTCCAGCATGGTGTGTCTGAGGCTCCCTGGAG GCTCCTGCATGGCAGTTCTGACAGTGACACTGATGGTGCTGAGCTCCCCACTGGCTTTGG CTGGGGACACCAGACCACGTTTCTTGGAGTACTCTACGTCTGAGTGTCATTTCTTCAATG GGACGGAGCGGGTGCGGTACCTGGACAGATACTTCCATAACCAGGAGGAGAACGTGCGCT TCGACAGCGACGTGGGGGAGTTCCGGGCGGTGACGGAGCTGGGGCGGCCTGATGCCGAGT ACTGGAACAGCCAGAAGGACCTCCTGGAGCAGAAGCGGGGCCGGGTGGACAACTACTGCA GACACAACTACGGGGTTGTGGAGAGCTTCACAGTGCAGCGGCGAGTCCATCCTAAGGTGA CTGTGTATCCTTCAAAGACCCAGCCCCTGCAGCACCATAACCTCCTGGTCTGTTCTGTGA GTGGTTTCTATCCAGGCAGCATTGAAGTCAGGTGGTTCCGGAATGGCCAGGAAGAGAAGA CTGGGGTGGTGTCCACAGGCCTGATCCACAATGGAGACTGGACCTTCCAGACCCTGGTGA TGCTGGAAACAGTTCCTCGGAGTGGAGAGGTTTACACCTGCCAAGTGGAGCACCCAAGCG TGACAAGCCCTCTCACAGTGGAATGGAGAGCACGGTCTGAATCTGCACAGAGCAAGATGC TGAGTGGAGTCGGGGGCTTTGTGCTGGGCCTGCTCTTCCTTGGGGCCGGGCTGTTCATCT ACTTCAGGAATCAGAAAGGACACTCTGGACTTCAGCCAAGAGGATTCCTGAGCTGAAGTG CAGATGACACATTCAAAGAAGAACTTTCTGCCCCAGCTTTGCAGGATGAAAAGCTTTCCC TCCTGGCTGTTATTCTTCCACAAGAGAGGGCTTTCTCAGGACCTGGTTGCTACTGGTTCA GCAACTGCAGAAAATGTCCTCCCTTGTGGCTTCCTCAGCTCCTGTTCTTGGCCTGAAGCC CCACAGCTTTGATGGCAGTGCCTCATCTTCAACTTTTGTGCTCCCCTTTGCCTAAACCCT ATGGCCTCCTGTGCATCTGTACTCACCCTGTACCA (SEQ ID NO: 35)

[0353] As used herein, the term "HLA-DRB5" refers to the gene encoding the HLA class II histocompatibility antigen, DR beta 5 chain. The terms "HLA-DRB5" and "HLA class II histocompatibility antigen, DR beta 5 chain" include the wild-type form of the HLA-DRB5 gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type HLA-DRB5. An example of such a variant is a nucleic acid having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type HLA-DRB5 nucleic acid sequence (e.g., SEQ ID NO: 36, ENA Accession No. M20429). SEQ ID NO: 36 is the wild-type gene sequence encoding the HLA-DRB5 protein and is shown below. CCAGCATGGTGTGTCTGAAGCTCCCTGGAGGTTCCTACATGGCAAAGCTGACAGTGACAC TGATGGTGCTGAGCTCCCCACTGGCTTTGGCTGGGGACACCCGACCACGTTTCTTGCAGC AGGATAAGTATGAGTGTCATTTCTTCAACGGGACGGAGCGGGTGCGGTTCCTGCACAGAG ACATCTATAACCAAGAGGAGGACTTGCGCTTCGACAGCGACGTGGGGGAGTACCGGGCGG TGACGGAGCTGGGGCGGCCTGACGCTGAGTACTGGAACAGCCAGAAGGACTTCCTGGAAG ACAGGCGCGCCGCGGTGGACACCTACTGCAGACACAACTACGGGGTTGGTGAGAGCTTCA CAGTGCAGCGGCGAGTTGAGCCTAAGGTGACTGTGTATCCTGCAAGGACCCAGACCCTGC AGCACCACAACCTCCTGGTCTGCTCTGTGAATGGTTTCTATCCAGGCAGCATTGAAGTCA GGTGGTTCCGGAACAGCCAGGAAGAGAAGGCTGGGGTGGTGTCCACAGGCCTGATTCAGA ATGGAGACTGGACCTTCCAGACCCTGGTGATGCTGGAAACAGTTCCTCGAAGTGGAGAGG TTTACACCTGCCAAGTGGAGCACCCAAGCGTGACGAGCCCTCTCACAGTGGAATGGAGAG CACAGTCTGAATCTGCACAGAGCAAGATGCTGAGTGGAGTCGGGGGCTTTGTGCTGGGCC TGCTCTTCCTTGGGGCCGGGCTATTCATCTACTTCAAGAATCAGAAAGGGCACTCTGGAC TTCACCCAACAGGACTCGTGAGCTGAAGTGCAGATGACCACATTCAAGGGGGAACCTTCT GCCCCAGCTTTGCATGATGAAAAGCTTTCCTGCTTGGCTCTTATTCTTCCACAAGAGAGG ACTTTCTCAGGCCCTGGTTGCTACCGGTTCAGCAACTCTGCAGAAAATGTCCATCCTTGT GGCTTCCTCAGCTCCTGCCCCTTGGCCTGAAGTCCCAGCATTGATGGCAGTGCCTCATCT TCAACTTTAGTGCTCCCCTTTACCTAACCCTACGGCCTCCCATGCATCTGTACTCCCCCT GTGTGCCACAAATGCACTACGTTATTAAATTTTTCTGAAGCCCAGAGTTAAAAATCATCT GTCCACCTGGCTCCAAAGACAAAAAATAAAAA (SEQ ID NO: 36)

[0354] As used herein, the term "IFIT1" refers to a gene encoding an interferon-inducible protein with tetratricopeptide repeat 1. The terms "IFIT1" and "interferon-inducible protein with tetratricopeptide repeat 1" include wild-type forms of the IFIT1 gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type IFIT1. An example of such a variant is a nucleic acid having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type IFIT1 nucleic acid sequence (e.g., SEQ ID NO: 37, ENA Accession No. X03557). SEQ ID NO: 37 is the wild-type gene sequence encoding the IFIT1 protein and is shown below. CCAGATCTCAGAGGAGCCTGGCTAAGCAAAACCCTGCAGAACGGCTGCCTAATTTACAGC AACCATGAGTACAAATGGTGATGATCATCAGGTCAAGGATAGTCTGGAGCAATTGAGATG TCACTTTACATGGGAGTTATCCATTGATGACGATGAAATGCCTGATTTAGAAAACAGAGT CTTGGATCAGATTGAATTCCTAGACACCAAATACAGTGTGGGAATACACAACCTACTAGC CTATGTGAAACACCTGAAAGGCCAGAATGAGGAAGCCCTGAAGAGCTTAAAAGAAGCTGA AAACTTAATGCAGGAAGAACATGACAACCAAGCAAATGTGAGGAGTCTGGTGACCTGGGG CAACTTTGCCTGGATGTATTACCACATGGGCAGACTGGCAGAAGCCCAGACTTACCTGGA CAAGGTGGAGAACATTTGCAAGAAGCTTTCAAATCCCTTCCGCTATAGAATGGAGTGTCC AGAAATAGACTGTGAGGAAGGATGGGCCTTGCTGAAGTGTGGAGGAAAGAATTATGAACG GGCCAAGGCCTGCTTTGAAAAGGTGCTTGAAGTGGACCCTGAAAACCCTGAATCCAGCGC TGGGTATGCGATCTCTGCCTATCGCCTGGATGGCTTTAAATTAGCCACAAAAAATCACAA GCCATTTTCTTTGCTTCCCCTAAGGCAGGCTGTCCGCTTAAATCCAGACAATGGATATAT TAAGGTTCTCCTTGCCCTGAAGCTTCAGGATGAAGGACAGGAAGCTGAAGGAGAAAAGTA CATTGAAGAAGCTCTAGCCAACATGTCCTCACAGACCTATGTCTTTCGATATGCAGCCAA GTTTTACCGAAGAAAAGGCTCTGTGGATAAAGCTCTTGAGTTATTAAAAAAGGCCTTGCA GGAAACACCCACTTCTGTCTTACTGCATCACCAGATAGGGCTTTGCTACAAGGCACAAAT GATCCAAATCAAGGAGGCTACAAAAGGGCAGCCTAGAGGGCAGAACAGAGAAAAGCTAGA CAAAATGATAAGATCAGCCATATTTCATTTTGAATCTGCAGTGGAAAAAAAGCCCACATT TGAGGTGGCTCATCTAGACCTGGCAAGAATGTATATAGAAGCAGGCAATCACAGAAAAGC TGAAGAGAATTTTCAAAAATTGTTATGCATGAAACCAGTGGTAGAAGAAACAATGCAAGA CATACATTTCTACTATGGTCGGTTTCAGGAATTTCAAAAGAAATCTGACGTCAATGCAAT TATCCATTATTTAAAAGCTATAAAAATAGAACAGGCATCATTAACAAGGGATAAAAGTAT CAATTCTTTGAAGAAATTGGTTTTAAGGAAACTTCGGAGAAAGGCATTAGATCTGGAAAG CTTGAGCCTCCTTGGGTTCGTCTACAAATTGGAAGGAAATATGAATGAAGCCCTGGAGTA CTATGAGCGGGCCCTGAGACTGGCTGCTGACTTTGAGAACTCTGTGAGACAAGGTCCTTA GGCACCCAGATATCAGCCACTTTCACATTTCATTTCATTTTATGCTAACATTTACTAATC ATCTTTTCTGCTTACTGTTTTCAGAAACATTATAATTCACTGTAATGATGTAATTCTTGA ATAATAAATCTGACAAAATATT (SEQ ID NO: 37)

[0355] As used herein, the term "IFIT3" refers to a gene encoding an interferon-inducible protein with tetratricopeptide repeats 3. The terms "IFIT3" and "interferon-inducible protein with tetratricopeptide repeats 3" include wild-type forms of the IFIT3 gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type IFIT3. An example of such a variant is a nucleic acid having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type IFIT3 nucleic acid sequence (e.g., SEQ ID NO: 38, ENA Accession No. AF026939). SEQ ID NO: 38 is the wild-type gene sequence encoding the IFIT3 protein and is shown below. GTGGAAACCTCTTCAGCATTTGCTTGGAATCAGTAAGCTAAAAACAAAATCAACCGGGAC CCCAGCTTTTCAGAACTGCAGGGAAACAGCCATCATGAGTGAGGTCACCAAGAATTCCCT GGAGAAAATCCTCCCACAGCTGAAATGCCATTTCACCTGGAACTTATTCAAGGAAGACAG TGTCTCAAGGGATCTAGAAGATAGAGTGTGTAACCAGATTGAATTTTTAAACACTGAGTT CAAAGCTACAATGTACAACTTGTTGGCCTACATAAAACACCTAGATGGTAAACAACGAGGC AGCCCTGGAATGCTTACGGCAAGCTGAAGAGTTAATCCAGCAAGAACATGCTGACCAAGC AGAAATCAGAAGTCTAGTCACTTGGGGAAACTACGCCTGGGTCTACTATCACTTGGGCAG ACTCTCAGATGCTCAGATTTATGTAGATAAGGTGAAACAAACCTGCAAGAAATTTTCAAA TCCATACAGTATTGAGTATTCTGAACTTGACTGTGAGGAAGGGTGGACACAACTGAAGTG TGGAAGAAATGAAAGGCGAAGGTGTGTTTTGAGAAGGCTCTGGAAGAAAAGCCCAACAA CCCAGAATTCTCCTCTGGGACTGGCAATTGCGATGTACCATCTGGATAATCACCCAGAGAA ACAGTTCTCTACTGATGTTTTGAAGCAGGCCATTGAGCTGAGTCCTGATAACCAATACGT CAAGGTTCTCTTGGGCCTGAAACTGCAGAAGATGAATAAAGAAGCTGAAGGAGAGCAGTT TGTTGAAGACCTTGGAAAAGTCTCCTTGCCAAACAGATGTCGTCCCGCAGTGCAGCCAA ATTTTACAGAAAAAGGTGACCTAGACAAAGCTATTGAACTGTTTCAACGGGTGTTGGA ATCCACACCAAAACAATGGCTCCTCTATCACCAGATTGGGTGCTGCTACAAGGCAAAAGT AAGACAAATGCAGAATACAGGAGAATCTGAAGCTAGTGGAAATAAAGAGATGATTGAAGC ACTAAAGCAATATGCTATGGACTATTCGAATAAAGCTCTTGAGAAGGGACTGAATCCTCT GAATGCATACTCCGATCTCGCTGAGTTCCTGGAGACGGAATGTTATCGACACCATTCAA TAAGGAAGTCCCTGATGCTGAAAAGCAACAATCCCATCAGCGCTACTGCAACCTTCAGAA ATATAATGGGAAGTCTGAAGACACTGCTGTGCAACATGGTTTAGAGGGTTTGTCCATAAG CAAAAAATCAACTGACAAGGAAGAGATCAAAGACCAACCACAGAATGTATCCGAAAATCT GCTTCCACAAAATGCACCAAATTATTGGTATCTTCAAGGATTAATTCATAAGCAGAATGG AGATCTGCTGCAAGCAGCCAAATGTTATGAGAAGGAACTGGGCCGCCTGCTAAGGGATGC CCCTTCAGGCATAGGCAGTATTTTCCTGTCAGCATCTGAGCTTGAGGATGGTAGTGAGGA AATGGGCCAGGGCGCAGTCAGCTCCAGTCCCAGAGAGCTCCTCTCTAACTCAGAGCAACT GAACTGAGACAGAGGAGGAAAACAGAGCATCAGAAGCCTGCAGTGGTGGTTGTGACGGGT AGGAGGATAGGAAGACAGGGGGCCCCAACCTGGGATTGCTGAGCAGGGAAGCTTTGCATG TTGCTCTAAGGTACATTTTTAAAGAGTTGTTTTTTGGCCGGGCGCAGTGGCTCATGCCTG TAATCCCAGCACTTTGGGAGGCCGAGGTGGGCGGATCACGAGGTCTGGAGTTTGAGACCA TCCTGGCTAACACAGTGAAATCCCGTCTCTACTAAAAATACAAAAAATTAGCCAGGCGTG GTGGCTGGCACCTGTAGTCCCAGCTACTTGGGAGGCTGAGGCAGGAGAATGGCGTGAACC TGGAAGGAAGAGGTTGCAGTGAGCCAAGATTGCGCCCCTGCACTCCAGCCTGGGCAACAG AGCAAGACTC (SEQ ID NO: 38)

[0356] As used herein, the term "IFITM3" refers to a gene encoding an interferon-induced transmembrane protein. The terms "IFITM3" and "interferon-induced transmembrane protein" include the wild-type form of the IFITM3 gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type IFITM3. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type IFITM3 nucleic acid sequence (e.g., SEQ ID NO: 39, NCBI Reference Sequence: NM_021034.2). SEQ ID NO: 39 is the wild-type gene sequence encoding the IFITM3 protein and is shown below. AGGAAAAGGAAACTGTTGAGAAACCGAAACTACTGGGGAAAGGGAGGGCTCACTGAGAACCATCCCAGTAACCCGACCGCCGCTGGTCTTCGCTGGACACCATGAATCACACTGTCCAAACCTTCTTCTCTCCTGTCAACAGTGGCCAGCCCCCCAACTATGAGATGCTCAAGGAGGAGCACGAGGTGGCTGTGCTGGGGGCGCCCCACAACCCTGCTCCCCCGACGTCCACCGTGATCCACATCCGCAGCGAGACCTCCGTGCCCGACCATGTCGTCTGGTCCCTGTTCAACACCCTCTTCATGAACCCCTGCTGCCTGGGCTTCATAGCATTCGCCTACTCCGTGAAGTCTAGGGACAGGAAGATGGTTGGCGACGTGACCGGGGCCCAGGCCTATGCCTCCACCGCCAAGTGCCTGAACATCTGGGCCCTGATTCTGGGCATCCTCATGACCATTCTGCTCATCGTCATCCCAGTGCTGATCTTCCAGGCCTATGGATAGATCAGGAGGCATCACTGAGGCCAGGAGCTCTGCCCATGACCTGTATCCCACGTACTCCAACTTCCATTCCTCGCCCTGCCCCCGGAGCCGAGTCCTGTATCAGCCCTTTATCCTCACACGCTTTTCTACAATGGCATTCAATAAAGTGCACGTGTTTCTGGTGCTAAAAAAAAAA (SEQ ID NO: 39)

[0357] As used herein, the term "IFNAR1" refers to the gene encoding interferon alpha / beta receptor 1. The terms "IFNAR1" and "interferon alpha / beta receptor 1" include wild-type forms of the IFNAR1 gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type IFNAR1. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type IFNAR1 nucleic acid sequence (e.g., SEQ ID NO: 40, ENA Accession No. J03171). SEQ ID NO: 40 is the wild-type gene sequence encoding the IFNAR1 protein and is shown below. TTAGGACGGGGCGATGGCGGCTGAGAGGAGCTGCGCGTGCGCGAACATGTAACTGGTGGG ATCTGCGGCGGCTCCCAGATGATGGTCGTCCTCCTGGGCGCGACGACCCTAGTGCTCGTC GCCGTGGGCCCATGGGTGTTGTCCGCAGCCGCAGGTGGAAAAAATCTAAAATCTCCTCAA AAAGTAGAGGTCGACATCATAGATGACAACTTTATCCTGAGGTGGAACAGGAGCGATGAG TCTGTCGGGAATGTGACTTTTTCATTCGATTATCAAAAAACTGGGATGGATAATTGGATA AAATTGTCTGGGTGTCAGAATATTACTAGTACCAAATGCAACTTTTCTTCACTCAAGCTG AATGTTTATGAAGAAATTAAATTGCGTATAAGAGCAGAAAAAGAAAACACTTCTTCATGG TATGAGGTTGACTCATTTACACCATTTCGCAAAGCTCAGATTGGTCCTCCAGAAGTACAT TTAGAAGCTGAAGATAAGGCAATAGTGATACACATCTCTCCTGGAACAAAAGATAGTGTT ATGTGGGCTTTGGATGGTTTAAGCTTTACATATAGCTTACTTATCTGGAAAAACTCTTCA GGTGTAGAAGAAAGGATTGAAAATATTTATTCCAGACATAAAATTTATAAACTCTCACCA GAGACTACTTATTGTCTAAAAGTTAAAGCAGCACTACTTACGTCATGGAAAATTGGTGTC TATAGTCCAGTACATTGTATAAAGACCACAGTTGAAAATGAACTACCCTCCACCAGAAAAT ATAGAAGTCAGTGTCCAAAATCAGAACTATGTTCTTAAATGGGATTATACATATGCAAAC ATGACCTTTCAAGTTCAGTGGCTCCACGCCTTTTTAAAAAGGAATCCTGGAAACCATTTG TATAAATGGAAACAAATACCTGACTGTGAAAATGTCAAAACTACCCAGTGTGTCTTTCCT CAAAACGTTTTCCAAAAGGAATTTACCTTCTCCGCGTACAAGCATCTGATGGAAATAAC ACATCTTTTTGGTCTGAAGAGATAAAGTTTGATACTGAAATACAAGCTTTCCTACTTCCT CCAGTCTTTAACATTAGATCCCTTAGTGATTCATTCCATATCTATATCGGTGCTCCAAAA CAGTCTGGAAACACGCCTGTGATCCAGGATTATCCACTGATTTATGAAATTATTTTTTGG GAAAACACTTCAAATGCTGAGAGAAAAATTATCGAGAAAAAAACTGATGTTACAGTTCCT AATTTGAAACCACTGACTGTATATTGTGTGAAAGCCAGAGCACACACCATGGATGAAAAG CTGAATAAAGCAGTGTTTTTAGTGACGCTGTATGTGAGAAAACAAACCAGGAAATACC TCTAAAATTTGGCTTATAGTTGGAATTTGTATTGCATTATTGCTCTCCCGTTTGTCATT TATGCTGCGAAAGTCTTCTTGAGATGCATCAATTATGTCTTCTTTCCATCACTTAAACCT TCTTCCAGTATAGATGAGTATTTCTCTGAAACAGCCATTGAAGAATCTTCTGCTTTCAACT TCTGAGACAAAATCGAAAAATGTTTCATAATTGAAAATATAAGCACAATTGCTACAGTA GAAGAAACTAATCAAACTGATGAAGATCATAAAAAATACAGTTCCCAAACTAGCCAAGAT TCAGGAAATTATTCTAATGAAGATGAAAGCGAAAGTAAAACAAGTGAAGAACTACAGCAG GACTTTGTATGACCAGAAATGAACTGTGTCAAGTATAAGGTTTTTCAGCAGGAGTTACAC TGGGAGCCTGAGGTCCTCACCTTCCTCTCAGTAACTACAGAGGACGTTTCCTGTTTAG GGAAAAAAAAACATCTTCAGATCATAGGTCCTAAAAAATACGGGCAAGCTCTTAACTATT TAAAAAATGAAATTACAGGCCCGGGCACGGTGGCTCACACCTGTAATCCCAGCACTTTGGG AGGCTGAGGCAGGCAGATCATGAGGTCAAGAGATCGAGACCAGCCTGGCCAACGTGGTGA AACCCCATCTCTACTAAAAATACAAAAATTAGCCGGGTAGTAGGTAGGCGCGCGCCTGTT GTCTTAGCTACTCAGGAGGCTGAGGCAGGAGAATCGCTTGAAAACAGGAGGTGGAGGTTG CAGTGAGCCGAGATCACGCCACTGCACTCCAGCCTGGTGACAGCGTGAGACTCTTTAAAA AAAGAAATTAAAAGAGTTGAGACAAACGTTTCCTACATTCTTTTCCATGTGTAAAATCAT GAAAAAGCCTGTCACCGGACTTGCATTGGATGAGATGAGTCAGACCAAAACAGTGGCCAC CCGTCTTCCTCCTGTGAGCCTAAGTGCAGCCGTGCTAGCTGCGCACCGTGGCTAAGGATG ACGTCTGTGTTCCTGTCCATCACTGATGCTGCTGGCTACTGCATGTGCCACACCTGTCTG TTCGCCATTCCTAACATTCTGTTTCATTCTTCCTCGGGAGATATTTCAAACATTTGGTCT TTTCTTTTAACACTGAGGGTAGGCCCTTAGGAAATTTATTTAGGAAAGTCTGAACACGTT ATCACTTGGTTTTCTGGAAAGTAGCTTACCCTAGAAAACAGCTGCAAATGCCAGAAAGAT GATCCCTAAAAATGTTGAGGGACTTCTGTTCATTCATCCCGAGAACATTGGCTTCCACAT CACAGTATCTACCCTTACATGGTTTAGGATTAAAGCCAGGCAATCTTTTACTATG (SEQ ID NO: 40)

[0358] As used herein, the term "IFNAR2" refers to the gene encoding interferon alpha / beta receptor 2. The terms "IFNAR2" and "interferon alpha / beta receptor 2" include wild-type forms of the IFNAR2 gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type IFNAR2. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type IFNAR2 nucleic acid sequence (e.g., SEQ ID NO: 41, ENA Accession No. X77722). SEQ ID NO: 41 is the wild-type gene sequence encoding the IFNAR2 protein and is shown below. GCTTTTGTCCCCCGCCCGCCGCTTCTGTCCGAGAGGCCGCCCGCGAGGCGCATCCTGACC GCGAGCGTCGGGTCCCAGAGCCGGGCGCGGCTGGGGCCCGAGGCTAGCATCTCTCGGGAG CCGCAAGGCGAGAGCTGCAAAGTTTAATTAGACACTTCAGAATTTTGATCACCTAATGTT GATTTCAGATGTAAAAGTCAAGAGAAGACTCTAAAAATAGCAAAGATGCTTTTGAGCCAG AATGCCTTCATCGTCAGATCACTTAATTTGGTTCTCATGGTGTATATCAGCCTCGTGTTT GGTATTTCATATGATTCGCCTGATTACACAGATGAATCTTGCACTTTCAAGATATCATTG CGAAATTTCCGGTCCATCTTATCATGGGAATTAAAAAACCACTCCATTGTACCAACTCAC TATACATTGCTGTATACAATCATGAGTAAACCAGAAGATTTGAAGGTGGTTAAGAACTGT GCAAATACCACAAGATCATTTTGTGACCTCACAGATGAGTGGAGAAGCACACACGAGGCC TATGTCACCGTCCTAGAAGGATTCAGCGGGAACACAACGTTGTTCAGTTGCTCACACAAT TTCTGGCTGGCCATAGACATGTCTTTTGAACCACCAGAGTTTGAGATTGTTGGTTTTACC AACCACATTAATGTGATGGTGAAATTTCCATCTATTGTTGAGGAAGAATTACAGTTTGAT TTATCTCTCGTCATTGAAGAACAGTCAGAGGGAATTGTTAAGAAGCATAAACCCGAAATA AAAGGAAACATGAGTGGAAATTTCACCTATATCATTGACAAGTTAATTCCAAACACGAAC TACTGTGTATCTGTTTATTTAGAGCACAGTGATGAGCAAGCAGTAATAAAGTCTCCCTTA AAATGCACCCTCCTTCCACCTGGGCCAGGAATCAGAATCAGCAGAATCTGCCAAAATAGGA GGAATAATTACTGTGTTTTTGATAGCATTGGTCTTGACAAGCACCATAGTGACACTGAAA TGGATTGGTTATATATGCTTAAGAAATAGCCTCCCCAAAGTCTTGAGGCAAGGTCTCACT AAGGGCTGGAATGCAGTGGCTATTCACAGGTGCAGTCATAATGCACTACAGTCTGAAACT CCTGAGCTCAAACAGTCGTCCTGCCTAAGCTTCCCCAGTAGCTGGGATTACAAGCGTGCA TCCCTGTGCCCCAGTGATTAAGTTTTATTATGTAGAAAATAAAGAGCAAACAGTTACAAA AGAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA (SEQ ID NO:41)

[0359] As used herein, the term "IGF1" refers to the gene encoding insulin-like growth factor I. The terms "IGF1" and "insulin-like growth factor I" include wild-type forms of the IGF1 gene, as well as variants of the wild-type IGF1 (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type IGF1 nucleic acid sequence (e.g., SEQ ID NO: 42, ENA Accession No. X00173). SEQ ID NO:42 is the wild-type gene sequence encoding the IGF1 protein and is shown below. CTTCAGAAGCAATGGGAAAAAATCAGCAGTCTTCCAACCCAATTATTTAAGTGCTGCTTTT GTGATTTCTTGAAGGTGAAGATGCACACCATGTCCTCCTCGCATCTCTTCTACCTGGCGC TGTGCCTGCTCACCTTCACCAGCTCTGCCACGGCTGGACCGGAGACGCTCTGCGGGGCTG AGCTGGTGGATGCTCTTCAGTTCGTGTGTGGAGACAGGGGCTTTTATTTCAACAAGCCCA CAGGGTATGGCTCCAGCAGTCGGAGGGCGCCTCAGACAGGTATCGTGGATGAGTGCTGCT TCCGGAGCTGTGATCTAAGGAGGCTGGAGATGTATTGCGCACCCCTCAAGCCTGCCAAGT CAGCTCGCTCTGTCCGTGCCCAGCGCCACACCGACATGCCCAAGACCCAGAAGGAAGTAC ATTTGAAGAACGCAAGTAGAGGGAGTGCAGGAAACAAGAACTACAGGATGTAGGAAGACC CTCCTGAGGAGTGAAGAGTGACATGCCACCGCAGGATCCTTTGCTCTGCACGAGTTACCT GTTAAACTTTGGAACACCTACCAAAAAATAAGTTTGATAACATTTAAAAGATGGGCGTTT CCCCCAATGAAATACACAAGTAAACATTCCAACATTGTCTTTAGGAGTGATTTGCACCTT GCAAAAATGGTCCTGGAGTTGGTAGATTGCTGTTGATCTTTTATCAATAATGTTCTATAG AAAAG (SEQ ID NO:42)

[0360] As used herein, the term "IL10RA" refers to the gene encoding the interleukin 10 receptor subunit alpha. The terms "IL10RA" and "interleukin 10 receptor subunit alpha" include wild-type forms of the IL10RA gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type IL10RA. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type IL10RA nucleic acid sequence (e.g., SEQ ID NO: 43, ENA Accession No. U00672). SEQ ID NO: 43 is the wild-type gene sequence encoding the IL10RA protein and is shown below. AAAGAGCTGGAGGCGCGCAGGCCGGCTCCGCTCCGGCCCCGGACGATGCGGCGCGCCCAG GATGCTGCCGTGCCTCGTAGTGCTGCTGGCGGCGCTCCTCAGCCTCCGTCTTGGCTCAGA CGCTCATGGGACAGAGCTGCCCAGCCCTCCGTCTGTGTGGTTTGAAGCAGAATTTTTCCA CCACATCCTCCACTGGACACCCATCCCAAATCAGTCTGAAAGTACCTGCTATGAAGTGGC GCTCCTGAGGTATGGAATAGAGTCCTGGAACTCCATCTCCAACTGTAGCCAGACCCTGTC CTATGACCTTACCGCAGTGACCTTGGACCTGTACCACAGCAATGGCTACCGGGCCAGAGT GCGGGCTGTGGACGGCAGCCGGCACTCCAACTGGACCGTCACCAACACCCGCTTCTCTGT GGATGAAGTGACTCTGACAGTTGGCAGTGTGAACCTAGAGATCCACAATGGCTTCATCCT CGGGAAGATTCAGCTACCCAGGCCCAAGATGGCCCCCGCGAATGACACATATGAAAGCAT CTTCAGTCACTTCCGAGAGTATGAGATTGCCATTCGCAAGGTGCCGGGAAACTTCACGTT CACACACAAGAAAGTAAAACATGAAAACTTCAGCCTCCTAACCTCTGGAGAAGTGGGAGA GTTCTGTGTCCAGGTGAAACCATCTGTCGCTTCCCGAAGTAACAAGGGGATGTGGTCTAA AGAGGAGTGCATCTCCCTCACCAGGCAGTATTTCACCGTGACCAACGTCATCATCTTCTT TGCCTTTGTCCTGCTGCTCTCCGGAGCCCTCGCCTACTGCCTGGCCCTCCAGCTGTATGT GCGGCGCCGAAAGAAGCTACCCAGTGTCCTGCTCTTCAAGAAGCCCAGCCCCTTCATCTT CATCAGCCAGCGTCCCTCCCCAGAGACCCAAGACACCATCCACCCGCTTGATGAGGAGGC CTTTTTGAAGGTGTCCCCAGAGCTGAAGAACTTGGACCTGCACGGCAGCACAGACAGTGG CTTTGGCAGCACCAAGCCATCCCTGCAGACTGAAGAGCCCCAGTTCCTCCTCCCTGACCC TCACCCCCAGGCTGACAGAACGCTGGGAAACGGGGAGCCCCCTGTGCTGGGGGACAGCTG CAGTAGTGGCAGCAGCAATAGCACAGACAGCGGGATCTGCCTGCAGGAGCCCAGCCTGAG CCCCAGCACAGGGCCCACCTGGGAGCAACAGGTGGGGAGCAACAGCAGGGGCCAGGATGA CAGTGGCATTGACTTAGTTCAAAACTCTGAGGGCCGGGCTGGGGACACACAGGGTGGCTC GGCCTTGGGCCACCACAGTCCCCCGGAGCCTGAGGTGCCTGGGGAAGAAGACCCAGCTGC TGTGGCATTCCAGGGTTACCTGAGGCAGACCAGATGTGCTGAAGAGAAGGCAACCAAGAC AGGCTGCCTGGAGGAAGAATCGCCCTTGACAGATGGCCTTGGCCCCAAATTCGGGAGATG CCTGGTTGATGAGGCAGGCTTGCATCCACCAGCCCTGGCCAAGGGCTATTTGAAACAGGA TCCTCTAGAAATGACTCTGGCTTCCTCAGGGGCCCCAACGGGACAGTGGAACCAGCCCAC TGAGGAATGGTCACTCCTGGCCTTGAGCAGCTGCAGTGACCTGGGAATATCTGACTGGAG CTTTGCCCATGACCTTGCCCCTCTAGGCTGTGTGGCAGCCCCAGGTGGTCTCCTGGGCAG CTTTAACTCAGACCTGGTCACCCTGCCCCTCATCTCTAGCCTGCAGTCAAGTGAGTGACT CGGGCTGAGAGGCTGCTTTTGATTTTAGCCATGCCTGCTCCTCTGCCTGGACCAGGAGGA GGGCCCTGGGGCAGAAGTTAGGCACGAGGCAGTCTGGGCACTTTTCTGCAAGTCCACTGG GGCTGGCCCAGCCAGGCTGCAGGGCTGGTCAGGGTGTCTGGGGCAGGAGGAGGCCAACTC ACTGAACTAGTGCAGGGTATGTGGGTGGCACTGACCTGTTCTGTTGACTGGGGCCCTGCA GACTCTGGCAGAGCTGAGAAGGGCAGGGACCTTCTCCCTCCTAGGAACTCTTTCCTGTAT CATAAAGGATTATTTGCTCAGGGGAACCATGGGGCTTTCTGGAGTTGTGGTGAGGCCACC AGGCTGAAGTCAGCTCAGACCCAGACCTCCCTGCTTAGGCCACTCGAGCATCAGAGCTTC CAGCAGGAGGAAGGGCTGTAGGAATGGAAGCTTCAGGGCCTTGCTGCTGGGGTCATTTTT AGGGGAAAAAGGAGGATATGATGGTCACATGGGGAACCTCCCCTCATCGGGCCTCTGGGG CAGGAAGCTTGTCACTGGAAGATCTTAAGGTATATATTTTCTGGACACTCAAACACATCA TAATGGATTCACTGAGGGGAGACAAAGGGAGCCGAGACCCTGGATGGGGCTTCCAGCTCA GAACCCATCCCTCTGGTGGGTACCTCTGGCACCCATCTGCAAATATCTCCCTCTCTCCAA CAAATGGAGTAGCATCCCCCTGGGGCACTTGCTGAGGCCAAGCCACTCACATCCTCACTT TGCTGCCCCACCATCTTGCTGACAACTTCCAGAGAAGCCATGGTTTTTTGTATTGGTCAT AACTCAGCCCTTTGGGCGGCCTCTGGGCTTGGGCACCAGCTCATGCCAGCCCCAGAGGGT CAGGGTTGGAGGCCTGTGCTTGTGTTTGCTGCTAATGTCCAGCTACAGACCCAGAGGATA AGCCACTGGGCACTGGGCTGGGGTCCCTGCCTTGTTGGTGTTCAGCTGTGTGATTTTGGA CTAGCCACTTGTCAGAGGGCCTCAATCTCCCATCTGTGAAATAAGGACTCCACCTTTAGG GGACCCTCCATGTTTGCTGGGTATTAGCCAAGCTGGTCCTGGGAGAATGCAGATACTGTC CGTGGACTACCAAGCTGGCTTGTTTCTTATGCCAGAGGCTAACAGATCCAATGGGAGTCC ATGGTGTCATGCCAAGACAGTATCAGACACAGCCCCAGAAGGGGGCATTATGGGCCCTGC CTCCCCATAGGCCATTTGGACTCTGCCTTCAAACAAAGGCAGTTCAGTCCACAGGCATGG AAGCTGTGAGGGGACAGGCCTGTGCGTGCCATCCAGAGTCATCTCAGCCCTGCCTTTCTC TGGAGCATTCTGAAAACAGATATTCTGGCCCAGGGAATCCAGCCATGACCCCCACCCCTC TGCCAAAGTACTCTTAGGTGCCAGTCTGGTAACTGAACTCCCTCTGGAGGCAGGCTTGAG GGAGGATTCCTCAGGGTTCCCTTGAAAGCTTTATTTATTTATTTTGTTCATTTATTTATT GGAGAGGCAGCATTGCACAGTGAAAGAATTCTGGATATCTCAGGAGCCCCGAAATTCTAG CTCTGACTTTGCTGTTTCCAGTGGTATGACCTTGGAGAAGTCACTTATCCTCTTGGAGCC TCAGTTTCCTCATCTGCAGAATAATGACTGACTTGTCTAATTCATAGGGATGTGAGGTTC TGCTGAGGAAATGGGTATGAATGTGCCTTGAACACAAAGCTCTGTCAATAAGTGATACAT GTTTTTTATTCCAATAAATTGTCAAGACCACA (SEQ ID NO: 43)

[0361] As used herein, the term "IL1A" refers to the gene encoding interleukin-1 alpha. The terms "IL1A" and "interleukin-1 alpha" include the wild-type form of the IL1A gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type IL1A. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type IL1A nucleic acid sequence (e.g., SEQ ID NO: 44, ENA Accession No. X02531). SEQ ID NO: 44 is the wild-type gene sequence encoding the IL1A protein and is shown below. ATGGCCAAAGTTCCAGACATGTTTGAAGACCTGAAGAACTGTTACAGTGAAAATGAAGAA GACAGTTCCTCCATTGATCATCTGTCTCTGAATCAGAAATCCTTCTATCATGTAAGCTAT GGCCCACTCCATGAAGGCTGCATGGATCAATCTGTGTCTCTGAGTATCTCTGAAACCTCT AAAACATCCAAGCTTACCTTCAAGGAGAGCATGGTGTAGTAGCAACCAACGGGAAGGTT CTGAAGAAGAGACGGTTGAGTTTAAGCCAATCCATCACTGATGATGACCTGGAGGCCATC GCCAATGACTCAGAGGAAGAAATCATCAAGCCTAGGTCAGCACCTTTTAGCTTCCTGAGC AATGTGAAATACAACTTTATGAGGATCATCAAATACGAATTCATCCTGAATGACGCCCTC AATCAAAGTATAATTCGAGCCAATGATCAGTACCTCACGGCTGCTGCATTACATAATCTG GATGAAGCAGTGAAATTTGACATGGGTGCTTATAAGTCATCAAAGGATGATGCTAAAATT ACCGTGATTCTAAGAATCTCAAAAACTCAATTGTATGTGACTGCCCAAGATGAAGACCAA CCAGTGCTGCTGAAGGAGATGCCTGAGATACCCAAAACCATCACAGGTAGTGAGACCAAC CTCCTCTTCTTCTGGGAAACTCACGGCACTAAGAACTATTTCACATCAGTTGCCCATCCA AACTTGTTTATTGCCACAAAGCAAGACTACTGGGTGTGCTTGGCAGGGGGGCCACCCTCT ATCACTGACTTTCAGATACTGGAAAACCAGGCGTAGGTCTGGAGTCTCACTTGTCTCACT TGTGCAGTGTTGACAGTTCATATGTACCATGTACATGAAGAAGCTAAATCCTTTACTGTT AGTCATTTGCTGAGCATGTACTGAGCCTTGTAATTCTAAATGAATGTTTACACTCTTTGT AAGAGTGGAACCAACACTAACATATAATGTTGTTATTTAAAGAACACCCTATATTTTGCA TAGTACCAATCATTTTAATTATTATTCTTCATAACAATTTTTAGGAGGACCAGAGCTACTG ACTATGGCTACCAAAGACTCTACCCATATTACAGATGGGCAAATTAAGGCATAAGAAA ACTAAGAAATATGCACAATAGCAGTTGAAACAAGAAGCCACAGACCTAGGATTTCATGAT TTCATTTCAACTGTTTGCCTTCTGCTTTTAAGTTGCTGATGAACTCTTAATCAAATAGCA TAAGTTTCTGGGACCTCAGTTTTATCATTTTCAAAATGGAGGGAATAATACCTAAGCCTT CCTGCCGCAACAGTTTTTTATGCTAATCAGGGAGGTCATTTTGGTAAAATACTTCTCGAA GCCGAGCCTCAAGATGAAGGCAAAGCACGAAATGTTATTTTTTAATTATTATTTATATAT GTATTTATAAATATATTTAAGATAATTATAATATACTATATTTATGGGAACCCCTTCATC CTCTGAGTGTGACCAGGCATCCTCCACAATAGCAGACAGTGTTTTCTGGGATAAGTAAGT TTGATTTCATTAATACAGGGCATTTTGGTCCAAGTTGTGCTTATCCCATAGCCAGGAAAC TCTGCATTCTAGTACTTGGGAGACCTGTAATCATATAATAAATGTACATTAATTACCTTG AGCCAGTAATTGGTCCGATCTTTGACTCTTTTGCCATTAAACTTACCTGGGCATTCTTGT TTCATTCAATTCCACCTGCAATCAAGTCCTACAAGCTAAAATTAGATGAACTCAACTTTG ACAACCATAGACCACTGTTATCAAAACTTTCTTTTCTGGAATGTAATCAATGTTTCTTCT AGGTTCTAAAAATTGTGATCAGACCATAATGTTACATTATTATCAACAATAGTGATTGAT AGAGTGTTATCAGTCATAACTAAATAAAGCTTGCAAGTGAGGGAGTCATTTCATTGGCGT TTGAGTCAGCAAAGAAGTCAAG (SEQ ID NO: 44)

[0362] As used herein, the term "IL1B" refers to a gene encoding interleukin-1 beta. The terms "IL1B" and "interleukin-1 beta" include wild-type forms of the IL1B gene, as well as variants of wild-type IL1B (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type IL1B nucleic acid sequence (e.g., SEQ ID NO: 45, ENA Accession No. X02770). SEQ ID NO:45 is the wild-type gene sequence encoding the IL1B protein and is shown below. ACAAACCTTTTCGAGGCAAAAGGCAAAAAAGGCTGCTCTGGGATTCTCTTCAGCCAATCT TCAATGCTCAAGTGTCTGAAGCAGCCATGGCAGAAGTACCTAAGCTCGCCAGTGAAATGA TGGCTTATTACAGTGGCAATGAGGATGACTTGTTCTTTGAAGCTGATGGCCCTAAACAGA TGAAGTGCTCCTTCCAGGACCTGGACCTCTGCCCTCTGGATGGGCGGCATCCAGCTACGAA TCTCCGACCACCACTACAGCAAGGGCTTCAGGCAGGCCGCGTCAGTTGTTGTGGCCATGG ACAAGCTGAGGAAGATGCTGGTTCCCTGCCCACAGACCTTCCAGGAGAATGACCTGAGCA CCTTCTTTCCCTTCATCTTTGAAGAAGAACCTATCTTCTTCGACACATGGGATAACGAGG CTTATGTGCACGATGCACCTGTACGATCACTGAACTGCACGCTCCGGGACTCACAGCAAA AAAGCTTGGTGATGTCTGGTCCATATGAACTGAAAGCTCTCCACCTCCAGGGACAGGATA TGGAGCAACAAGTGGTGTTCTCCATGTCCTTTGTACAAGGAGAAGAAAGTAATGACAAAA TACCTGTGGCCTTGGGCCTCAAGGAAAAGAATCTGTACCTGTCCTGCGTGTTGAAAGATG ATAAGCCCACTCTACAGCTGGAGAGTGTAGATCCCAAAAATTACCCAAAGAAGAAGATGG AAAAGCGATTTGTCTTCAACAAGATAGAAATCAATAACAAGCTGGAATTTGAGTCTGCCC AGTTCCCCAACTGGTACATCAGCACCTCTCAAGCAGAAAACATGCCCGTCTTCCTGGGAG GGACCAAAGGCGGCCAGGATATAACTGACTTCACCATGCAATTTGTGTCTTCCTAAAGAG AGCTGTACCCAGAGAGTCCTGTGCTGAATGTGGACTCAATCCCTAGGGCTGGCAGAAAGG GAACAGAAAGGTTTTTGAGTACGGCTATAGCCTGGACTTTCCTGTTGTCTACACCAATGC CCAACTGCCTGCCTTAGGGTAGTGCTAAGAGGATCTCCTGTCCATCAGCCAGGACAGTCA GCTCTCTCCTTTCAGGGCCAATCCCAGCCCTTTTGTTGAGCCAGGCCTCTCTCACCTCTC CTACTCACTTAAAGCCCGCCTGACAGAAACCAGGCCACATTTTGGTTCTAAGAAACCCTC CTCTGTCATTCGCTCCCACATTCTGATGAGCAACCGCTTCCCTATTTATTTATTTATTTG TTTGTTTGTTTTGATTCATTGGTCTAATTTATTCAAAGGGGGCAAGAAGTAGCAGGTGTCT GTAAAAGAGCCTAGTTTTTAATAGCTATGGAATCAATTCAATTTGGACTGGTGTGCTCTC TTTAAATCAAGTCCTTTAATTAAGACTGAAAATATATAAGCTCAGATTATTTAAATGGGA ATATTTATAAAATGAGCAAATATCATACTGTTCAATGGTTCTCAAATAAACTTCACT (SEQ ID NO:45)

[0363] As used herein, the term "IL1RAP" refers to the gene encoding the interleukin 1 receptor accessory protein. The terms "IL1RAP" and "interleukin 1 receptor accessory protein" include the wild-type form of the IL1RAP gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type IL1RAP. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type IL1RAP nucleic acid sequence (e.g., SEQ ID NO: 46, ENA Accession No. AF029213). SEQ ID NO: 46 is the wild-type gene sequence encoding the IL1RAP protein and is shown below. TCTCAAAGGATGACACTTCTGTGGTGTGTAGTGAGTCTCTACTTTTATGGAATCCTGCAA AGTGATGCCTCAGAACGCTGCGATGACTGGGGACTAGACACCATGAGGCAAATCCAAGTG TTTGAAGATGAGCCAGCTCGCATCAAGTGCCCACTCTTTGAACACTTCTTGAAATTCAAC TACAGCACAGCCCATTCAGCTGGCCTTACTCTGATCTGGTATTGGACTAGGCAGGACCGG GACCTTGAGGAGCCAATTAACTTCCGCCTCCCCGAGAACCGCATTAGTAAGGAGAAAGAT GTGCTGTGGTTCCGGCCCACTCTCCTCAATGACACTGGCAACTATACCTGCATGTTAAGG AACACTACATATTGCAGCAAAGTTGCATTTCCCTTGGAAGTTGTTCAAAAAGACAGCTGT TTCAATTCCCCCATGAAACTCCCAGTGCATAAACTGTATATAGAATATGGCATTCAGAGG ATCACTTGTCCAAATGTAGATGGATATTTTCCTTCCAGTGTCAAACCGACTATCACTTGG TATATGGGCTGTTATAAAATACAGAATTTTAATAATGTAATACCCGAAGGTATGAACTTG AGTTTCCTCATTGCCTTAATTTCAAATAATGGAAATTACACATGTGTTGTTACATATCCA GAAAATGGACGTACGTTTCATCTCACCAGGACTCTGACTGTAAAGGTAGTAGGCTCTCCA AAAAATGCAGTGCCCCCTGTGATCCATTCACCTAATGATCATGTGGTCTATGAGAAAGAA CCAGGAGAGGAGCTACTCATTCCCTGTACGGTCTATTTTAGTTTTCTGATGGATTCTCGC AATGAGGTTTGGTGGACCATTGATGGAAAAAAACCTGATGACATCACTATTGATGTCACC ATTAACGAAAGTATAAGTCATAGTAGAACAGAAGATGAAACAAGAACTCAGATTTTGAGC ATCAAGAAAGTTACCTCTGAGGATCTCAAGCGCAGCTATGTCTGTCATGCTAGAAGTGCC AAAGGCGAAGTTGCCAAAGCAGCCAAGGTGAAGCAGAAAGTGCCAGCTCCAAGATACACA GTGGAACTGGCTTGTGGTTTTGGAGCCACAGTCCTGCTAGTGGTGATTCTCATTGTTGTT TACCATGTTTACTGGCTAGAGATGGTCCTATTTTACCGGGCTCATTTTGGAACAGATGAA ACCATTTTAGATGGAAAAGAGTATGATATTTATGTATCCTATGCAAGGAATGCGGAAGAA GAAGAATTTGTATTACTGACCCTCCGTGGAGTTTTGGAGAATGAATTTGGATACAAGCTG TGCATCTTTGACCGAGACAGTCTGCCTGGGGGAATTGTCACAGATGAGACTTTGAGCTTC ATTCAGAAAAGCAGACGCCTCCTGGTTGTTCTAAGCCCCAACTACGTGCTCCAGGGAACC CAAGCCCTCCTGGAGCTCAAGGCTGGCCTAGAAAATATGGCCTCTCGGGGCAACATCAAC GTCATTTTAGTACAGTACAAAGCTGTGAAGGAAACGAAGGTGAAAGAGCTGAAGAGGGCT AAGACGGTGCTCACGGTCATTAAATGGAAAGGGGAAAAATCCAAGTATCCACAGGGCAGG TTCTGGAAGCAGCTGCAGGTGGCCATGCCAGTGAAGAAAAGTCCCAGGCGGTCTAGCAGT GATGAGCAGGGCCTCTCGTATTCATCTTTGAAAAATGTATGAAAGGAATAATGAAAAGGA (SEQ ID NO: 46)

[0364] As used herein, the term "INPP5D" refers to the gene encoding phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1. The terms "INPP5D" and "phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1" include wild-type forms of the INPP5D gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type INPP5D. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type INPP5D nucleic acid sequence (e.g., SEQ ID NO: 47, ENA Accession No. X98429). SEQ ID NO: 47 is the wild-type gene sequence encoding the INPP5D protein and is shown below. GTTGCTGTCGCCGTTGCTGTCGGCCGAGGCCACCAAGAGGCAACGGGCGGCAGGTTGCAG TGGAGGGGCCTCCGCTCCCCTCGGTGGTGTGTGGGTCCTGGGGGTGCCTGCCGGCCCAGC CGAGGAGGCCCACGCCCACCATGGTCCCCTGCTGGAACCATGGCAACATCACCCGCTCCA AGGCGGAGGAGCTGCTTTCCAGGACAGGCAAGGACGGGAGCTTCCTCGTGCGTGCCAGGCG AGTCCATCTCCCGGGCATACGCGCTCTGCGTGCTGTATCGGAATTGCGTTTACACTTACA GAATTCTGCCCAATGAAGATGATAAATTCACTGTTCAGGCATCCGAAGGCGTCTCCATGA GGTTCTTCACCAAGCTGGACCAGCTCATCGAGTTTTACAAGAAGGAAAACATGGGGCTGG TGACCCATCTGCAATACCCTGTGCCGCTGGAGGAAGAGGACACAGGCGACGACCCTGAGG AGGACACAGAAAGTGTCGTGTCTCCACCCGAGCTGCCCCCAAGAAACATCCCGCTGACTG CCAGCTCCTGTGAGGCCAAGGAGGTTCCTTTTTCAAACGAGAATCCCCGAGCGACCGAGA CCAGCCGGCCGAGCCTCTCCGAGACATTGTTCCAGCGACTGCAAAGCATGGACACCAGTG GGCTTCCAGAAGAGCATCTTAAGGCCATCCAAGATTATTTAAGCACTCAGCTCGCCCAGG ACTCTGAATTTGTGAAGACAGGGTCCAGCAGTCTTCCTCACCTGAAGAAACTGACCACAC TGCTCTGCAAGGAGCTCTATGGAGAAGTCATCCGGACCCTCCCATCCCTGGAGTCTCTGC AGAGGTTATTTGACCAGCAGCTCTCCCCGGGCCTCCGTCCACGTCCTCAGGTTCCTGGTG AGGCCAATCCCATCAACATGGTGTCCAAGCTCAGCCAACTGACAAGCCTGTTGTCGTCCA TTGAAGACAAGGTCAAGGCCTTGCTGCACGAGGGTCCTGAGTCTCCGCACCGGCCCTCCC TTATCCCTCCAGTCACCTTTGAGGTGAAGGCAGAGTCTCTGGGGATTCCTCAGAAAATGC AGCTCAAAGTCGACGTTGAGTCTGGGAAACTGATCATTAAGAAGTCCAAGGATGGTTCTG AGGACAAGTTCTACAGCCACAAGAAAATCCTGCAGCTGATTAAGTCACAGAAATTTCTGA ATAAGTTGGTGATCTTGGTGGAAACGGAGAAGGAGAAGATCCTGCGGAAGGAATATGTTT TTGCTGACTCCAAAAAGAGAGAAGGCTTCTGCCAGCTCCTGCAGCAGATGAAGAACAAGC ACTCAGAGCAGCCGGAGCCCGACATGATCACCATCTTCATCGGCACCTGGAACATGGGTA ACGCCCCCCCTCCCAAGAAGATCACGTCCTGGTTTCTCTCCAAGGGGCAGGGAAAGACGC GGGACGACTCTGCGGACTACATCCCCCATGACATTTACGTGATCGGCACCCAAGAGGACC CCCTGAGTGAGAAGGAGTGGCTGGAGATCCTCAAACACTCCCTGCAAGAAATCACCAGTG TGACTTTTAAAACAGTCGCCATCCACACGCTCTGGAACATCCGCATCGTGGTGCTGGCCA AGCCTGAGCACGAGAACCGGATCAGCCACATCTGTACTGACAACGTGAAGACAGGCATTG CAAACACACTGGGGAACAAGGGAGCCGTGGGGGTGTCGTTCATGTTCAATGGAACCTCCT TAGGGTTCGTCAACAGCCACTTGACTTCAGGAAGTGAAAAGAAACTCAGGCGAAACCAAA ACTATATGAACATTCTCCGGTTCCTGGCCCTGGGCGACAAGAAGCTGAGTCCCTTTAACA TCACTCACCGCTTCACGCACCTCTTCTGGTTTGGGGATCTTAACTACCGTGTGGATCTGC CTACCTGGGAGGCAGAAACCATCATCCAGAAAATCAAGCAGCAGCAGTACGCAGACCTCC TGTCCCACGACCAGCTGCTCACAGAGAGGAGGGAGCAGAAGGTCTTCCTACACTTCGAGG AGGAAGAAATCACGTTTGCCCCAACCTACCGTTTTGAGAGACTGACTCGGGACAAATACG CCTACACCAAGCAGAAAGCGACAGGGATGAAGTACAACTTGCCTTCCTGGTGTGACCGAG TCCTCTGGAAGTCTTATCCCCTGGTGCACGTGGTGTGTCAGTCTTATGGCAGTACCAGCG ACATCATGACGAGTGACCACAGCCCTGTCTTTGCCACATTTGAGGCAGGAGTCACTTCCC AGTTTGTCTCCAAGAACGGTCCCGGGACTGTTGACAGCCAAGGACAGATTGAGTTTCTCA GGTGCTATGCCACATTGAAGACCAAGTCCCAGACCAAATTCTACCTGGAGTTCCACTCGA GCTGCTTGGAGAGTTTTGTCAAGAGTCAGGAAGGAGAAAATGAAGAAGGAAGTGAGGGGG AGCTGGTGGTGAAGTTTGGTGAGACTCTTCCAAAGCTGAAGCCCATTATCTCTGACCCTG AGTACCTGCTAGACCAGCACATCCTCATCAGCATCAAGTCCTCTGACAGCGACGAATCCT ATGGCGAGGGCTGCATTGCCCTTCGGTTAGAGGCCACAGAAACGCAGCTGCCCATCTACA CGCCTCTCACCCACCATGGGGAGTTGACAGGCCACTTCCAGGGGGAGATCAAGCTGCAGA CCTCTCAGGGCAAGACGAGGGAGAAGCTCTATGACTTTGTGAAGACGGAGCGTGATGAAT CCAGTGGGCCAAAGACCCTGAAGAGCCTCACCAGCCACGACCCCATGAAGCAGTGGGAAG TCACTAGCAGGGCCCCTCCGTGCAGTGGCTCCAGCATCACTGAAATCATCAACCCCAACT ACATGGGAGTGGGGCCCTTTGGGCCACCAATGCCCCTGCACGTGAAGCAGACCTTGTCCC CTGACCAGCAGCCCACAGCCTGGAGCTACGACCAGCCGCCCAAGGACTCCCCGCTGGGGC CCTGCAGGGGAGAAAGTCCTCCGACACCTCCCGGCCAGCCGCCCATATCACCCAAGAAGT TTTTACCCTCAACAGCAAACCGGGGTCTCCCTCCCAGGACACAGGAGTCAAGGCCCAGTG ACCTGGGGAAGAACGCAGGGGACACGCTGCCTCAGGAGGACCTGCCGCTGACGAAGCCCG AGATGTTTGAGAACCCCCTGTATGGGTCCCTGAGTTCCTTCCCTAAGCCTGCTCCCAGGA AGGACCAGGAATCCCCCAAAATGCCGCGGAAGGAACCCCCGCCCTGCCCGGAACCCGGCA TCTTGTCGCCCAGCATCGTGCTCACCAAAGCCCAGGAGGCTGATCGCGGCGAGGGGCCCG GCAAGCAGGTGCCCGCGCCCCGGCTGCGCTCCTTCACGTGCTCATCCTCTGCCGAGGGCA GGGCGGCCGGCGGGGACAAGAGCCAAGGGAAGCCCAAGACCCCGGTCAGCTCCCAGGCCC CGGTGCCGGCCAAGAGGCCCATCAAGCCTTCCAGATCGGAAATCAACCAGCAGACCCCGC CCACCCCGACGCCGCGGCCGCCGCTGCCAGTCAAGAGCCCGGCGGTGCTGCACCTCCAGC ACTCCAAGGGCCGCGACTACCGCGACAACACCGAGCTCCCGTATCACGGCAAGCACCGGC CGGAGGAGGGGCCACCAGGGCCTCTAGGCAGGACTGCCATGCAGTGAAGCCCTCAGTGAG CTGCCACTGAGTCGGGAGCCCAGAGGAACGGCGTGAAGCCACTGGACCCTCTCCCGGGAC CTCCTGCTGGCTCCTCCTGCCCAGCTTCCTATGCAAGGCTTTGTGTTTTCAGGAAAGGGC CTAGCTTCTGTGTGGCCCACAGAGTTCACTGCCTGTGAGACTTAGCACCAAGTGCTGAGG CTGGAAGAAAAACGCACACCAGACGGGCAACAAACAGTCTGGGTCCCCAGCTCGCTCTTG GTACTTGGGACCCCAGTGCCTTGTTGAGGGCGCCATTCTGAAGAAAGGAACTGCAGCGCC GATTTGAGGGTGGAGATATAGATAATAATAATATTAATAATAATAATGGCCACATGGATC GAACACTCATGGTGTGCCAAGTGCTGTGCTAAGTGCTTTACGAACATTCGTCATATCAGG ATGACCTCGAGAGCTGAGGCTCTAGCACCTAAAACCACGTGCCCAAACCCACCAGTTTAA AACGGTGTGTGTTCGGAGGGGTGAAAGCATTAAGAAGCCCAGTGCCCTCCTGGAGTGAGA CAAGGGCTCGGCCTTAAGGAGCTGAAGAGTCTGGGTAGCTTGTTTAGGGTACAAGAAGCC TGTTCTGTCCAGCTTCAGTGACACAAGCTGCTTTAGCTAAAGTCCCGCGGGTTCCGGCAT GGCTAGGCTGAGAGCAGGGATCTACCTGGCTTCTCAGTTCTTTGGTTGGAAGGAGCAGGA AATCAGCTCCTATTCTCCAGTGGAGAGATCTGGCCTCAGCTTGGGCTAGAGATGCCAAGG CCTGTGCCAGGTTCCCTGTGCCCTCCTCGAGGTGGGCAGCCATCACCAGCCACAGTTAAG CCAAGCCCCCCAACATGTATTCCATCGTGCTGGTAGAAGAGTCTTTGCTGTTGCTCCCGA AAGCCGTGCTCTCCAGCCTGGCTGCCAGGGAGGGTGGGCCTCTTGGTTCCAGGCTCTTGA AATAGTGCAGCCTTTTCTTCCTATCTCTGTGGCTTTCAGCTCTGCTTCCTTGGTTATTAG GAGAATAGATGGGTGATGTCTTTCCTTATGTTGCTTTTTCAACATAGCAGAATTAATGTA GGGAGCTAAATCCAGTGGTGTGTGTGAATGCAGAAGGGAATGCACCCCACATTCCCATGA TGGAAGTCTGCGTAACCAATAAATTGTGCCTTTCTCACTCAAAACC (SEQ ID NO: 47)

[0365] As used herein, the term "ITGAM" refers to the gene encoding the integrin subunit alpha M. The terms "ITGAM" and "integrin subunit alpha M" include wild-type forms of the ITGAM gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type ITGAM. An example of such a variant is a nucleic acid having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type ITGAM nucleic acid sequence (e.g., SEQ ID NO: 48, NCBI Reference Sequence: NM_000632.3). SEQ ID NO: 48 is the wild-type gene sequence encoding the ITGAM protein and is shown below. (SEQ ID NO:48)

[0366] As used herein, the term "ITGAX" refers to a gene encoding integrin alpha-X. The terms "ITGAX" and "integrin alpha-X" include wild-type forms of the ITGAX gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type ITGAX. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type ITGAX nucleic acid sequence (e.g., SEQ ID NO: 49, ENA Accession No. M81695). SEQ ID NO: 49 is the wild-type gene sequence encoding the ITGAX protein and is shown below. GAATTCCTGCCACTCTTCCTGCAACGGCCCAGGAGCTCAGAGCTCCACATCTGACCTTCT AGTCATGACCAGGACCAGGGCAGCACTCCTCCTGTTCACAGCCTTAGCAACTTCTCTAGG TTTCAACTTGGACACAGAGGAGCTGACAGCCTTCCGTGTGCAGCGCTGGGTTTGGAGA CAGCGTGGTCCAGTATGCCAACTCCTGGGTGGTGGTTGGAGCCCCCCAAAAGATAACAGC TGCCAACCAAACGGGTGGCCTCTACCAGTGTGCTACAGCACTGGTGCCTGTGAGCCCAT CGGCCTGCAGGTGCCCCCGGAGGCCGTGAACATGTCCCTGGGCCTGTCCCTGGCGTCTAC CACCAGCCCTTCCCAGCTGCTGGCCTGCGGCCCCACCGTGCACCACGAGTGCGGGAGGAA CATGTACCTCACCGGACTCTGCTTCCTCCTGGGCCCCACCCAGCTCACCCAGAGGCTCCC GGTGTCCAGGCAGGAGTGCCCAAGACAGGAGCAGGACATTGTGTTCCTGATCGATGGCTC AGGCAGCATCTCCTCCCGCAACTTTGCCACGATGATGAACTTCGTGAGAGCTGTGATAAG CCAGTTCCAGAGACCCAGCACCCAGTTTTCCCTGATGCAGTTCTCCAACAAATTCCAAAC ACACTTCACTTTCGAGGAATTCAGGCGCACGTCAAACCCCCTCAGCCTGTTGGCTTCTGT TCACCAGCTGCAAGGGTTTACATACACGGCCACCGCCATCCAAAATGTCGTGCACCGATT GTTCCATGCCTCATATGGGGCCCGTAGGGATGCCACCAAAATTCTCATTGTCATCACTGA TGGGAAGAAAGAAGGCGACAGCCTGGATTATAAGGATGTCATCCCCATGGCTGATGCAGC AGGCATCATCCGCTATGCAATTGGGGTTGGATTAGCTTTTCAAAACAGAAATTCTTGGAA AGAATTAAATGACATTGCATCGAAGCCCTCCCAGGAACACATATTTAAAGTGGAGGACTT TGATGCTCTGAAAGATATTCAAAACCAACTGAAGGAGAAGATCTTTGCCATTGAGGGTAC GGAGACCACAAGCAGTAGCTCCTTCGAATTGGAGATGGCACAGGAGGGCTTCAGCGCTGT GTTCACACCTGATGGCCCCGTTCTGGGGGCTGTGGGGAGCTTCACCTGGTCTGGAGGTGC CTTCCTGTACCCCCCAAATATGAGCCCTACCTTCATCAACATGTCTCAGGAGAATGTGGA CATGAGGGACTCTTACCTGGGTTACTCCACCGAGCTGGCCCTCTGGAAAGGGGTGCAGAG CCTGGTCCTGGGGGCCCCCCGCTACCAGCACACCGGGAAGGCTGTCATCTTCACCCAGGT GTCCAGGCAATGGAGGATGAAGGCCGAAGTCACGGGGACTCAGATCGGCTCCTACTTCGG GGCCTCCCTCTGCTCCGTGGACGTAGACACCGACGGCAGCACCGACCTGGTCCTCATCGG GGCCCCCCATTACTACGAGCAGACCCGAGGGGGCCAGGTGTCTGTGTGTCCCTTGCCCAG GGGGTGGAGAAGGTGGTGGTGTGATGCTGTTCTCTACGGGGAGCAGGGCCACCCCTGGGG TCGCTTTGGGGCGGCTCTGACAGTGCTGGGGGATGTGAATGGGGACAAGCTGACAGACGT GGTCATCGGGGCCCCAGGAGAGGAGGAGAACCGGGGTGCTGTCTACCTGTTTCACGGAGT CTTGGGACCCAGCATCAGCCCCTCCCACAGCCAGCGGATCGCGGGCTCCCAGCTCTCCTC CAGGCTGCAGTATTTTGGGCAGGCACTGAGCGGGGGTCAAGACCTCACCCAGGATGGACT GGTGGACCTGGCTGTGGGGGCCCGGGGCCAGGTGCTCCTGCTCAGGACCAGACCTGTGCT CTGGGTGGGGGTGAGCATGCAGTTCATACCTGCCGAGATCCCCAGGTCTGCGTTTGAGTG TCGGGAGCAGGTGGTCTCTGAGCAGACCCTGGTACAGTCCAACATCTGCCTTTACATTGA CAAACGTTCTAAGAACCTGCTTGGGAGCCGTGACCTCCAAAGCTCTGTGACCTTGGACCT GGCCCTCGACCCTGGCCGCCTGAGTCCCCGTGCCACCTTCCAGGAAACAAAGAACCGGAG TCTGAGCCGAGTCCGAGTCCTCGGGCTGAAGGCACACTGTGAAAACTTCAACCTGCTGCT CCCGAGCTGCGTGGAGGACTCTGTGACCCCCATTACCTTGCGTCTGAACTTCACGCTGGT GGGCAAGCCCCTCCTTGCCTTCAGAAACCTGCGGCCTATGCTGGCCGCACTGGCTCAGAG ATACTTCACGGCCTCCCTACCCTTTGAGAAGAACTGTGGAGCCGACCATATCTGCCAGGA CAATCTCGGCATCTCCTTCAGCTTCCCAGGCTTGAAGTCCCTGCTGGTGGGGAGTAACCT GGAGCTGAACGCAGAAGTGATGGTGTGGAATGACGGGGAAGACTCCTACGGAACCACCAT CACCTTCTCCCACCCCGCAGGACTGTCCTACCGCTACGTGGCAGAGGGCCAGAAACAAGG GCAGCTGCGTTCCCTGCACCTGACATGTGACAGCGCCCCAGTTGGGAGCCAGGGCACCTG GAGCACCAGCTGCAGAATCAACCACCTCATCTTCCGTGGCGGCGCCCAGATCACCTTCTT GGCTACCTTTGACGTCTCCCCCAAGGCTGTCCTGGGAGACCGGCTGCTTCTGACAGCCAA TGTGAGCAGTGAGAACAACACTCCCAGGACCAGCAAGACCACCTTCCAGCTGGAGCTCCC GGTGAAGTATGCTGTCTACACTGTGGTTAGCAGCCACGAACAATTCACCAAATACCTCAA CTTCTCAGAGTCTGAGGAGAAGGAAAGCCATGTGGCCATGCACAGATACCAGGTCAATAA CCTGGGACAGAGGGACCTGCCTGTCAGCATCAACTTCTGGGTGCCTGTGGAGCTGAACCA GGAGGCTGTGTGGATGGATGTGGAGGTCTCCCACCCCCAGAACCCATCCCTTCGGTGCTC CTCAGAGAAAATCGCACCCCCAGCATCTGACTTCCTGGCGCACATTCAGAAGAATCCCGT GCTGGACTGCTCCATTGCTGGCTGCCTGCGGTTCCGCTGTGACGTCCCCTCCTTCAGCGT CCAGGAGGAGCTGGATTTCACCCTGAAGGGCAACCTCAGCTTTGGCTGGGTCCGCCAGAT ATTGCAGAAGAAGGTGTCGGTCGTGAGTGTGGCTGAAATTACGTTCGACACATCCGTGTA CTCCCAGCTTCCAGGACAGGAGGCATTTATGAGAGCTCAGACGACAACGGTGCTGGAGAA GTACAAGGTCCACAACCCCACCCCCCTCATCGTAGGCAGCTCCATTGGGGGTCTGTTGCT GCTGGCACTCATCACAGCGGTACTGTACAAAGTTGGCTTCTTCAAGCGTCAGTACAAGGA AATGATGGAGGAGGCAAATGGACAAATTGCCCCAGAAAACGGGACACAGACCCCCAGCCC GCCCAGTGAGAAATGATCCCTCTTTGCCTTGGACTTCTTCTCCCGCGATTTTCCCCACTT ACTTACCCTCACCTGTCAGGCTGACGGGGAGGAACCACTGCACCACCGAGAGAGGCTGGG ATGGGCCTGCTTCCTGTCTTTGGGAGAAAACGTCTTGCTTGGGAAGGGGCCTTTGTCTTG TCAAGGTTCCAACTGGAAACCCTTAGGACAGGGTCCCTGCTGTGTTCCCCAAAAGGACTT GACTTGCAATTTCTACCTAGAAATACATGGACAATACCCCCAGGCCTCAGTCTCCCTTCT CCCATGAGGCACGAATGATCTTTCTTTCCTTTCCTTTTTTTTTTTTTTCTTTTCTTTTTT TTTTTTTTTGAGACGGAGTCTCGCTCTGTCACCCAGGCTGGAGTGCAATGGCGTGATCTC GGCTCGCTGCAACCTCCGCCTCCCGGGTTCAAGTAATTCTGCTGTCTCAGCCTCCTGCGT AGCTGGGACTACAGGCACACGCCACCTCGCCCGGCCCGATCTTTCTAAAATACAGTTCTG AATATGCTGCTCATCCCCACCTGTCTTCAACAGCTCCCCATTACCCTCAGGACAATGTCT GAACTCTCCAGCTTCGCGTGAGAAGTCCCCTTCCATCCCAGAGGGTGGGCTTCAGGGCGC ACAGCATGAGAGCCTCTGTGCCCCCATCACCCTCGTTTCCAGTGAATTAGTGTCATGTCA GCATCAGCTCAGGGCTTCATCGTGGGGCTCTCAGTTCCGATTCCCCAGGCTGAATTGGGA GTGAGATGCCTGCATGCTGGGTTCTGCACAGCTGGCCTCCCGCGGTTGGGTCAACATTGC TGGCCTGGAAGGGAGGAGCGCCCTCTAGGGAGGGACATGGCCCCGGTGCGGCTGCAGCTC ACCAGCCCCAGGGGCAGAAGAGACCCAACCACTTCCTATTTTTTGAGGCTATGAATATAG TACCTGAAAAAATGCCAAGCACTAGATTATTTTTTTAAAAAGGCGTACTTTAAATGTTGT GTTAATACACATTAAAACATCGCACAAAAACGATGCATCTACCGCTCCTTGGGAAAATAAT CTGAAAGGTCTAAAAATAAAAAAGCCTTCTGTGG (SEQ ID NO:49)

[0367] As used herein, the term "LILRB4" refers to the gene encoding leukocyte immunoglobulin-like receptor subfamily B member 4. The terms "LILRB4" and "leukocyte immunoglobulin-like receptor subfamily B member 4" include wild-type forms of the LILRB4 gene, as well as variants of the wild-type LILRB4 (e.g., splice variants and polymorphisms). An example of such a variant is a nucleic acid having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type LILRB4 nucleic acid sequence (e.g., SEQ ID NO: 50, ENA Accession No. U91925). SEQ ID NO: 50 is the wild-type gene sequence encoding the LILRB4 protein and is shown below. TGAGATGAGAGCTGCCGACAGTTGGGGTCAAGGGAGGAGACGCCATGATCCCCACCTTC ACGGCTCTGCTCTGCCTCGGGCTGAGTCTGGGCCCCAGGACCCACATGCAGGCAGGGCCC CTCCCCAAACCCACCCTCTGGGCTGAGCCAGGCTCTGTGATCAGCTGGGGGAACTCTGTG ACCATCTGGTGTCAGGGGACCCTGGAGGCTCGGGAGTACCGTCTGGATAAAGAGGAAAGC CCAGCACCCTGGGACAGACAGAACCCACTGGAGCCCAAGAACAAGGCCAGATTCTCCATC CCATCCATGACAGAGGACTATGCAGGGAGATACCGCTGTTACTATCGCAGCCCTGTAGGC TGGTCACAGCCCAGTGACCCCCTGGAGCTGGTGATGACAGGAGCCTACAGTAAACCCACC CTTTCAGCCCTGCCGAGTCCTCTTGTGACCTCAGGAAAGAGCGTGACCCTGCTGTGTCAG TCACGGAGCCCAATGGACACTTTCCTTCTGATCAAGGAGCGGGCAGCCCATCCCCTACTG CATCTGAGATCAGAGCACGGAGCTCAGCAGCACCAGGCTGAATTCCCCATGAGTCCTGTG ACCTCAGTGCACGGGGGGACCTACAGGTGCTTCAGCTCACACGGCTTCTCCCACTACCTG CTGTCACACCCCAGTGACCCCCTGGAGCTCATAGTCTCAGGATCCTTGGAGGGTCCCAGG CCCTCACCCACAAGGTCCGTCTCAACAGCTGCAGGCCCTGAGGACCAGCCCCTCATGCCT ACAGGGTCAGTCCCCCACAGTGGTCTGAGAAGGCACTGGGAGGTACTGATCGGGGTCTTG GTGGTCTCCATCCTGCTTCTCTCCCTCCTCCTCTTCCTCCTCCTCCAACACTGGCGTCAG GGAAAACACAGGACATTGGCCCAGAGACAGGCTGATTTCCAACGTCCTCCAGGGGCTGCC GAGCCAGAGCCCAAGGACGGGGGCCTACAGAGGAGGTCCAGCCCAGCTGCTGACGTCCAG GGAGAAAACTTCTGTGCTGCCGTGAAGAACACACAGCCTGAGGACGGGGTGGAAATGGAC ACTCGGCAGAGCCCACACGATGAAGACCCCCAGGCAGTGACGTATGCCAAGGTGAAACAC TCCAGACCTAGGAGAGAAATGGCCTCTCCTCCCTCCCCACTGTCTGGGGAATTCCTGGAC ACAAAGGACAGACAGGCAGAAGAGGACAGACAGATGGACACTGAGGCTGCTGCATCTGAA GCCCCCCAGGATGTGACCTACGCCCAGCTGCACAGCTTTACCCTCAGACAGAAGGCAACT GAGCCTCCTCCATCCCAGGAAGGGGCCTCTCCAGCTGAGCCCAGTGTCTATGCCACTCTG GCCATCCACTAATCCAGGGGGGACCCAGACCCCACAAGCCATGGAGACTCAGGACCCCAG AAGGCATGGAAGCTGCCTCCAGTAGACATCACTGAACCCCAGCCAGCCCAGACCCCTGAC ACAGACCACTAGAAGATTCCGGGAACGTTGGGAGTCACCTGATTCTGCAAAGATAAATAA TATCCCTGCATTATCAAAATAAAGTAGCAGACCTCTCAATTCA (SEQ ID NO: 50)

[0368] As used herein, the term "LPL" refers to a gene encoding lipoprotein lipase. The terms "LPL" and "lipoprotein lipase" include wild-type forms of the LPL gene, as well as variants of wild-type LPL (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type LPL nucleic acid sequence (e.g., SEQ ID NO: 51, ENA Accession No. M15856). SEQ ID NO:51 is the wild-type gene sequence encoding the LPL protein and is shown below. CCCCTCTTCCTCCTCCTCAAGGGAAAGCTGCCCACTTCTAGCTGCCCTGCCATCCCCTTT AAAGGGCGACTTGCTCAGCGCCAAACCGCGGCTCCAGCCCTCTCCAGCCTCCGGCTCAGC CGGCTCATCAGTCGGTCCGCGCCTTGCAGCTCCTCCAGAGGGACGCGCCCCGAGATGGAG AGCAAAGCCCTGCTCGTGCTGACTCTGGCCGTGTGGCTCCAGAGTCTGACCGCCTCCCGC GGAGGGGTGGCCGCCGCCGACCAAAGAAGAGATTTTATCGACATCGAAAGTAAATTTGCC CTAAGGACCCCTGAAGACACAGCTGAGGACACTTGCCACCTCATTCCCGGAGTAGCAGAG TCCGTGGCTACCTGTCATTTCAATCACAGCAGCAAAACCTTCATGGTGATCCATGGCTGG ACGGTAACAGGAATGTATGAGAGTTGGGTGCCAAAACTTGTGGCCGCCCTGTACAAGAGA GAACCAGACTCCAATGTCATTGTGGTGGACTGGCTGTCACGGGCTCAGGAGCATTACCCA GTGTCCGCGGGCTACACCAAACTGGTGGGACAGGATGTGGCCCGGTTTATCAACTGGATG GAGGAGGAGTTTAACTACCCTCTGGACAATGTCCATCTCTTGGGATACAGCCTTGGAGCC CATGCTGCTGGCATTGCAGGAAGTCTGACCAATAAGAAAGTCAACAGAATTACTGGCCTC GATCCAGCTGGACCTAACTTTGAGTATGCAGAAGCCCCGAGTCGTCTTTCTCCTGATGAT GCAGATTTTGTAGACGTCTTACACACATTCACCAGAGGGTCCCCTGGTCGAAGCATTGGA ATCCAGAAACCAGTTGGGCATGTTGACATTTACCCGAATGGAGGTACTTTTCAGCCAGGA TGTAACATTGGAGAAGCTATCCGCGTGATTGCAGAGAGAGGACTTGGAGATGTGGACCAG CTAGTGAAGTGCTCCCACGAGCGCTCCATTCATCTCTTCATCGACTCTCTGTTGAATGAA GAAAATCCAAGTAAGGCCTACAGGTGCAGTTCCAAGGAAGCCTTTGAGAAAGGGCTCTGC TTGAGTTGTAGAAAGAACCGCTGCAACAATCTGGGCTATGAGATCAATAAAGTCAGAGCC AAAAGAAGCAGCAAAATGTACCTGAAGACTCGTTCTCAGATGCCCTACAAAGTCTTCCAT TACCAAGTAAAGATTCATTTTTCTGGGACTGAGAGTGAAACCCATACCAATCAGGCCTTT GAGATTTCTCTGTATGGCACCGTGGCCGAGAGTGAGAACATCCCATTCACTCTGCCTGAA GTTTCCACAAATAAGACCTACTCCTTCCTAATTTACACAGAGGTAGATATTGGAGAACTA CTCATGTTGAAGCTCAAATGGAAGAGTGATTCATACTTTAGCTGGTCAGACTGGTGGAGC AGTCCCGGCTTCGCCATTCAGAAGATCAGAGTAAGCAGGAGAGACTCAGAAAGGGTG ATTCTTCTGTTCTAGGGAGAAAGTGTCTCATTTGCAGAAAGGAAAGGCACCTGCGGTATTT GTGAAATGCCATGACAAGTCTCTGAATAAGAAGTCAGGCTGAAACTGGGCGAATCTACAG AACAAAGAACGGCATGTGAATTCTGTGAAGAATGAAGTGGAGGAAGTAACTTTTACAAAA CATACCCAGTGTTTGGGGTGTTTCAAGGTGGATTTTCCTGAATATTAATCCCAGCCCTA CCCTTGTTAGTTATTTTAGGAGACAGTCTCAAGCACTAAAAAGTGGCTAATTCAATTTAT GGGGTATAGTGGCCAAATAGCACATCCTCCAACGTTAAGACAGTGGATCATGAAAAGT GCTGTTTGTCCTTTGAGAAAGAAATAATTGTTTGAGCGCAGAGTAAAATAAGGCTCCTT CATGTGGCGTATTGGGCCATAGCCTATAATTGGTTAGAACCTCCTATTTTTTAATTGGAATT CTGGATCTTTCGGACTGAGGCCTTCTCAAACTTTACTCTAAGTCTCCAAGAATACAGAAA ATGCTTTTCCGCGGCACGAATCAGACTCATCTACACAGCAGTATGAATGATGTTTTAGAA TGATTCCCTCTTGCTATTGGAATGTGGTCCAGACGTCAACCAGGAACATGTAACTTGGAG AGGGACGAAGAAAGGGTCTGATAAACAGAGGTTTTAAACAGTCCCTACCATTGGCCTG CATCATGACAAAGTTACAAATTCAAGGAGATATAAAATCTAGATCAATTAATTCTTAATA GGCTTTATTCGTTTATTGCTTAATCCCTCTCTCCCCCTTCTTTTTTGTCTCAAGATTATAT TATAATAATGTTCTCTGGGTAGGTGTTGAAAATGAGCCTGTAATCCTCAGCTGACACATA ATTTGAATGGTGCAGAAAAAAAAAAAGATACCGTAATTTTATTATTAGATTCTCCAAATGA TTTTCATCAATTTAAAATCATTCAATATCTGACAGTTACTCTTCAGTTTTAGGCTTACCT TGGTCATGCTTCAGTTGTACTTCCAGTGCGTCTCTTTTGTTCCTGGCTTTGACATGAAAA GATAGGTTTTGAGTTCAAATTTTGCATTGTGTGAGCTTCTACAGATTTTAGACAAGGACCG TTTTTACTAAGTAAAGGGTGGAGAGGTTCCTGGGGTGGATTCCTAAGCAGTGCTTGTAA ACCATCGCGTGCAATGAGCCAGATGGAGTACCATGAGGGTTGTTATTTGTTGTTTTTAAC AACTAATCAAGAGTGAGTGAACAACTATTTATAAACTAGATCTCCTATTTTTCAGAATGC TCTTCTACGTATAAATATGAAATGATAAAGATGTCAAATATCTCAGAGGCTATAGCTGGG AACCCGACTGTGAAAGTATGTGATATCTGAACACATACTAGAAAGCTCTGCATGTGTGTT GTCCTTCAGCATAATTCGGAAGGGAAAACAGTCGATCAAGGGATGTATTGGAACATGTCG GAGTAGAAATTGTTCCTGATGTGCCAGAACTTCGACCCTTTCTCTGAGAGAGATGATCGT GCCTATAAATAGTAGGACCAATGTTGTGATTAACATCATCAGGCTTGGAATGAATTCTCT CTAAAAATAAAATGATGTATGATTTGTTGTTGGCATCCCCTTTATTAATTCATTAAATTT CTGGATTTGGGTTGTGACCCAGGGTGCATTAACTTAAAAGATTCACTAAAGCAGCACATA GCACTGGGAACTCTGGCTCCGAAAAACTTTGTTATATATATCAAGGATGTTCTGGCTTTA CATTTTATTTATTAGCTGTAAATACATGTGTGGATGTGTAAATGGAGCTTGTACATATTG GAAAGGTCATTGTGGCTATCTGCATTTATAAATGTGTGGTGCTAACTGTATGTGTCTTTA TCAGTGATGGTCTCACAGAGCCAACTCACTCTTATGAAATGGGCTTTAACAAAACAAGAA AGAAACGTACTTAACTGTGTGAAGAAATGGAATCAGCTTTTAATAAAATTGACAACATTT TATTACCAC (SEQ ID NO: 51)

[0369] As used herein, the term "MEF2C" refers to the gene encoding muscle cell-specific enhancer factor 2 C. The terms "MEF2C" and "muscle cell-specific enhancer factor 2C" include wild-type forms of the MEF2C gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type MEF2C. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type MEF2C nucleic acid sequence (e.g., SEQ ID NO: 52, ENA Accession No. L08895). SEQ ID NO: 52 is the wild-type gene sequence encoding the MEF2C protein and is shown below. GAATTCCCAGCTCTCTGCTCGCTCTGCTCGCAGTCACAGACACTTGAGCACACGCGTACA CCCAGACATCTTCGGGCTGCTATTGGATTGACTTTGAAGGTTCTGTGTGGGTCGCCGTGG CTGCATGTTTGAATCAGGTGGAGAAGCACTTCAACGCTGGACGAAGTAAAGATTATTGTT GTTATTTTTTTTTTCTCTCTCTCTCTCTTAAGAAAGGAAAATATCCCAAGGACTAATC TGATCGGGTCTTCCTTCATCAGGAACGAATGCAGGAATTTGGGAACTGAGCTGTGCAAGT GCTGAAGAAGGAGATTTGTTTGGAGGAAACAGGAAAGAGAAAGAAAAGGAAGGAAAAAAT ACATAATTTCAGGGACGAGAGAGAGAAGAAAAACGGGGACTATGGGGAGAAAAAAGATTC AGATTACGAGGATTATGGATGAACGTAACAGACAGGTGACATTTACAAAGAGGAAATTTG GGTTGATGAAGAAGGCTTATGAGCTGAGCGTGCTGTGTGACTGTGAGATTGCGCTGATCA TCTTCAACAGCACCAACAAGCTGTTCCAGTATGCCAGCACCGACATGGACAAAGTGCTTC TCAAGTACACGGAGTACAACGAGCCGCATGAGAGCCGGACAAACTCAGACATCGTGGAGA CGTTGAGAAAGAAGGGCCTTAATGGCTGTGACAGCCCAGACCCCGATGCGGACGATTCCG TAGGTCACAGCCCTGAGTCTGAGGACAAGTACAGGAAAATTAACGAAGATATTGATCTAA TGATCAGCAGGCAAAGATTGTGTGCTGTTCCACCTCCCAACTTCGAGATGCCAGTCTCCA TCCCAGTGTCCAGCCACAACAGTTTGGTGTACAGCAACCCTGTCAGCTCACTGGGAAACC CCAACCTATTGCCACTGGCTCACCCTTCTCTGCAGAGGAATAGTATGTCTCCTGGTGTAA CACATCGACCTCCAAGTGCAGGTAACACAGGTGGTCTGATGGGTGGAGACCTCACGTCTG GTGCAGGCACCAGTGCAGGGAACGGGTATGGCAATCCCCGAAACTCACCAGGTCTGCTGG TCTCACCTGGTAACTTGAACAAGAATATGCAAGCAAAATCTCCTCCCCCAATGAATTTAG GAATGAATAACCGTAAACCAGATCTCCGAGTTCTTATTCCACCAGGCAGCAAGAATACGA TGCCATCAGTGTCTGAGGATGTCGACCTGCTTTTGAATCAAAGGATAAATAACTCCCAGT CGGCTCAGTCATTGGCTACCCCAGTGGTTTCCGTAGCAACTCCTACTTTACCAGGACAAG GAATGGGAGGATATCCATCAGCCATTTCAACAACATATGGTACCGAGTACTCTCTGAGTA GTGCAGACCTGTCATCTCTGTCTGGGTTTAACACCGCCAGCGCTCTTCACCTTGGTTCAG TAACTGGCTGGCAACAGCAACACCTACATAACATGCCACCATCTGCCCTCAGTCAGTTGG GAGCTTGCACTAGCACTCATTTATCTCAGAGTTCAAATCTCTCCCTGCCTTCTACTCAAA GCCTCAACATCAAGTCAGAACCTGTTTCTCCTCCTAGAGACCGTACCACCACCCCTTCGA GATACCCACAACACACGCGCCACGAGGCGGGGAGATCTCCTGTTGACAGCTTGAGCAGCT GTAGCAGTTCGTACGACGGGAGCGACCGAGAGGATCACCGGAACGAATTCCACTCCCCCA TTGGACTCACCAGACCTTCGCCGGACGAAAGGGAAAGTCCCTCAGTCAAGCGCATGCGAC TTTCTGAAGGATGGGCAACATGATCAGATTATTACTTACTAGTTTTTTTTTTTTTCTTGC AGTGTGTGTGTGTGCTATACCTTAATGGGGAAGGGGGGTCGATATGCATTATATGTGCCG TGTGTGGAAAAAAAAAAAGTCAGGTACTCTGTTTTGTAAAAGTACTTTTAAATTGCCTCA GTGATACAGTATAAAGATAAACAGAAATGCTGAGATAAGCTTAGCACTTGAGTTGTACAA CAGAACACTTGTACAAAATAGATTTTAAGGCTAACTTCTTTTCACTGTTGTGCTCCTTTG CAAAATGTATGTTACAATAGATAGTGTCATGTTGCAGGTTCAACGTTATTTACATGTAAA TAGACAAGGAAAACATTTGCCAAAAGCGGCAGATCTTTACTGAAAGAGAGAGGCAGCTGT TATGCAACATATAGAAAAATGTATAGATGCTTGGACAGACCCGGTAATGGGTGGCCATTG GTAAATGTTAGGAACACACCAGGTCACCTGACATCCCAAGAATGCTCACAAACCTGCAGG CATATCATTGGCGTATGGCACTCATTAAAGGATCAGAGACCATTAAAAGAGGACCATA CCTATTAAAAAAAATGTGGAGTTGGAGGGCTAACATATTTAATTAAATAAATAAATAAA TCTGGGTCTGCATCTCTTATTAAATAAAAATATAAAAATATGTACATTACATTTTGCTTA TTTTCATATAAAGGTAAGACAGAGTTTGCAAAGCATTTGTGGCTTTTTTGTAGTTTACTT AAGCCAAATGTGTTTTTTTCCCCTTGATAGCTTCGCTAATATTTTAAACAGTCCTGTAA AAAACCAAAGGACTTTTTGTATAGAAAGCACTACCCTAAGCCATGAAGAACTCCATGC TTTGCTAACCAAGATAACTGTTTTCTCTTTGTAGAAGTTTTGTTTTTGAAATGTGTATTT CTAATTATATAAAAATATTAAGAATCTTTTAAAAAAATCTGTGAAATTAACATGCTTGTGT ATAGCTTTCTAATATATATAATATTATGGTAATAGCAGAAGTTTTGTTATCTTAATAGCG GGAGGGGGGTATATTTGTGCAGTTGCACATTTGAGTAACTATTTTCTTTCTGTTTTCTTT TACTCTGCTTACATTTTATAAGTTTAAGGTCAGCTGTCAAAAGGATAACCTGTGGGGTTA GAACATATCACATTGCAACACCCTAAATTGTTTTTAATACATTAGCAATCTATTGGGTCA ACTGACATCCATTGTATATACTAGTTTCTTTCATGCTATTTTTATTTTGTTTTTTGCATT TTTATCAAATGCAGGGCCCCTTTCTGATCTCACCATTTCACCATGCATCTTGGAATTCAG TAAGTGCATATCCTAACTTGCCCATATTCTAAATCATCTGGTTGGTTTTCAGCCTAGATE TTGATACGCTTTTTAGAAATATGCCCAGAATAGAAAAGCTATGTTGGGGCACATGTCCTG CAAATATGGCCCTAGAAACAAGTGATATGGAATTTACTTGGTGAATAAGTTATAAATTCC CACAGAAGAAAAATGTGAAAGACTGGGTGCTAGACAAGAAGGAAGCAGGTAAAGGGATAG TTGCTTTGTCATCCGTTTTTAATTATTTTAACTGACCCTTGACAATCTTGTCAGCAAATAT AGGACTGTTGAACAATCCCGGTGTTGTCAGGACCCCCAAATGTCACTTCTGCATAAAGCAT GTATGTCATCTATTTTTTCTTCAATAAAGAGATTTAATAGCCATTTCAAGAAATCCCATA AAGAACCTCTCTATGTCCCTTTTTTTAATTTAAAAAAATGACTCTTGTCTAATATTCGTC TATAAGGGATTAATTTTCAGACCCTTTAATAAGTGAGTGCCATAAGAAAGTCAATATATA TTGTTTAAAAGATATTTCAGTCTAGGAAAGATTTTCCTTCTCTTGGAATGTGAAGATCTG TCGATTCATCTCCAATCATATGCATTGACATACACAGCAAAGAAGATATAGGCAGTAATA TCAACACTGCTATATCATGTGTAGGACATTTCTTATCCATTTTTTCTCTTTTACTTGCAT AGTTGCTATGTGTTTCTCATTGTAAAAGGCTGCCGCTGGGTGGCAGAAGCCAAGAGACCT TATTAACTAGGCTATATTTTTCTTAACTTGATCTGAAATCCACAATTAGACCACAATGCA CCTTTGGTTGTATCCATAAAGGATGCTAGCCTGCCTTGTACTAATGTTTTATATATT (SEQ ID NO: 52)

[0370] As used herein, the term "MMP12" refers to the gene encoding macrophage metalloelastase. The terms "MMP12" and "macrophage metalloelastase" include wild-type forms of the MMP12 gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type MMP12. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type MMP12 nucleic acid sequence (e.g., SEQ ID NO: 53, ENA Accession No. L23808). SEQ ID NO: 53 is the wild-type gene sequence encoding the MMP12 protein and is shown below. TAGAAGTTTACAATGAAGTTTCTTCTAATACTGCTCCTGCAGGCCACTGCTTCTGGAGCT CTTCCCCTGAACAGCTCTACAAGCCTGGAAAAAAATAATGTGCTATTTGGTGAGAGATAC TTAGAAAAATTTTATGGCCTTGAGATAAACAAACTTCCAGTGACAAAAATGAAATATAGT GGAAACTTAATGAAGGAAAAAATCCAAGAAATGCAGCACTTCTTGGGTCTGAAAGTGACC GGGCAACTGGACACATCTACCCTGGAGATGATGCACGCACCTCGATGTGGAGTCCCCGAT CTCCATCATTTCAGGGAAATGCCAGGGGGGCCCGTATGGAGGAAACATTATATCACCTAC AGAATCAATAATTACACACCTGACATGAACCGTGAGGATGTTGACTACGCAATCCGGAAA GCTTTCCAAGTATGGAGTAATGTTACCCCCTTGAAATTCAGCAAGATTAACACAGGCATG GCTGACATTTTGGTGGTTTTTGCCCGTGGAGCTCATGGAGACTTCCATGCTTTTGATGGC AAAGGTGGAATCCTAGCCCATGCTTTTGGACCTGGATCTGGCATTGGAGGGGATGCACAT TTCGATGAGGACGAATTCTGGACTACACATTCAGGAGGCACAAACTTGTTCCTCACTGCT GTTCACGAGATTGGCCATTCCTTAGGTCTTGGCCATTCTAGTGATCCAAAGGCTGTAATG TTCCCCACCTACAAATATGTCGACATCAACACATTTCGCCTCTCTGCTGATGACATACGT GGCATTCAGTCCCTGTATGGAGACCCAAAAGAGAACCAACGCTTGCCAAATCCTGACAAT TCAGAACCAGCTCTCTGTGACCCCAATTTGAGTTTTGATGCTGTCACTACCGTGGGAAAT AAGATCTTTTTCTTCAAAGACAGGTTCTTCTGGCTGAAGGTTTCTGAGAGACCAAAGACC AGTGTTAATTTAATTTCTTCCTTATGGCCAACCTTGCCATCTGGCATTGAAGCTGCTTAT GAAATTGAAGCCAGAAATCAAGTTTTTCTTTTTAAAGATGACAAATACTGGTTAATTAGC AATTTAAGACCAGAGCCAAATTATCCCAAGAGCATACATTCTTTTGGTTTTCCTAACTTT GTGAAAAAAATTGATGCAGCTGTTTTTAACCCACGTTTTTATAGGACCTACTTCTTTGTA GATAACCAGTATTGGAGGTATGATGAAAGGAGACAGATGATGGACCCTGGTTATCCCAAA CTGATTACCAAGAACTTCCAAGGAATCGGGCCTAAAATTGATGCAGTCTTCTATTCTAAA AACAAATACTACTATTTCTTCCAAGGATCTAACCAATTTGAATATGACTTCCTACTCCAA CGTATCACCAAAACACTGAAAAGCAATAGCTGGTTTGGTTGTTAGAAATGGTGTAATTAA TGGTTTTTGTTAGTTCACTTCAGCTTAATAAGTATTTATTGCATATTTGCTATGTCCTCA GTGTACCACTACTTAGAGATATGTATCATAAAAATAAAATCTGTAAACCATAGGTAATGA TTATATAAAATACATAATATTTTTCAATTTTGAAAACTCTAATTGTCCATTCTTGCTTGA CTCTACTATTAAGTTTGAAAATAGTTACCTTCAAAGCAAGATAATTCTATTTGAAGCATG CTCTGTAAGTTGCTTCCTAACATCCTTGGACTGAGAAATTATACTTACTTCTGGCATAAC TAAAATTAAGTATATATATTTTGGCTCAAATAAAATTG (SEQ ID NO: 53)

[0371] As used herein, the term "MS4A4A" refers to a gene encoding transmembrane 4 domain A4A. The terms "MS4A4A" and "transmembrane 4 domain A4A" include wild-type forms of the MS4A4A gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type MS4A4A. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type MS4A4A nucleic acid sequence (e.g., SEQ ID NO: 54, NCBI Reference Sequence: NM_148975.2). SEQ ID NO: 54 is the wild-type gene sequence encoding the MS4A4A protein and is shown below. (SEQ ID NO:54)

[0372] As used herein, the term "MS4A6A" refers to the gene encoding the transmembrane 4 domain subfamily A member 6A. The terms "MS4A6A" and "transmembrane 4 domain subfamily A member 6A" include wild-type forms of the MS4A6A gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type MS4A6A. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type MS4A6A nucleic acid sequence (e.g., SEQ ID NO:55, ENA Accession No. AB013104). SEQ ID NO:55 is the wild-type gene sequence encoding the MS4A6A protein and is shown below. GAGAACCAGAGTTAAAACCTCTTTGGAGCTTCTGAGGACTCAGCTGGAACCAACGGGCAC AGTTGGCAACACCATCATGACATCACAACCTGTTCCCAATGAGACCATCATAGTGCTCCC ATCAAATGTCATCAACTTCTCCCAAGCAGAGAAACCCGAACCCACCAACCAGGGGCAGGA TAGCCTGAAGAAACATCTACACGCAGAAATCAAAGTTATTGGGACTATCCAGATCTTGTG TGGCATGATGGTATTGAGCTTGGGGATCATTTTGGCATCTGCTTCCTTCTCTCCAAATTT TACCCAAGTGACTTCTACACTGTTGAACTCTGCTTACCCATTCATAGGACCCTTTTTTT TATCATCTCTGGCTCTCTATCAATCGCCACAGAGAAAAGGTTAACCAAGCTTTTGGTGCA TAGCAGCCTGGTTGGAAGCATTCTGAGTGCTCTGTCTGCCCTGGTGGGTTTCATTATCCT GTCTGTCAAACAGGCCACCTTAAATCCTGCCTCACTGCAGTGGAACTCTCTCTCTGATGC TGATTTGCACTCTGCTGGAATTCTGCCTAGCTGTGCTCACTGCTGTGCTGCGGTGGAAAC AGGCTTACTCTGACTTCCCTGGGAGTGGACTTTTCCTGCCTCACAGTTACATTGGTAATT CTGGCATGTCCTCAAAAATGACTCATGACTGTGGATATGAAGAACTATTGACTTCTTAAG AAAAAAGGGAGAAATATTAATCAGAAAGTTGATTCTTATGATAATATGGAAAAGTTAACC ATTATAGAAAAGCAAAGCTTGAGTTTCCTAAATGTAAGCTTTTAAAGTAATGAACATTAA AAAAAACCATTATTTCACTGTC (SEQ ID NO: 55)

[0373] As used herein, the term "NLRP3" refers to the gene encoding the NACHT, LRR, and PYD domain-containing protein 3. The terms "NLRP3" and "NACHT, LRR, and PYD domain-containing protein 3" include wild-type forms of the NLRP3 gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type NLRP3. An example of such a variant is a nucleic acid having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type NLRP3 nucleic acid sequence (e.g., SEQ ID NO: 56, ENA Accession No. AF410477). SEQ ID NO: 56 is the wild-type gene sequence encoding the NLRP3 protein, and is shown below. GTAGATGAGGAAACTGAAGTTGAGGAATAGTGAAGAGTTTGTCCAATGTCATAGCCCCGT AATCAACGGGACAAAAATTTTCTTGCTGATGGGTCAAGATGGCATCGTGAAGTGGTTGTT CACCGTAAACTGTAATACAATCCTGTTTATGGATTTGTTTGCATATTTTTCCCCCCATAG GGAAACCTTTTTTTCCATGGCTCAGGACACACTCCTGGATCGAGCCAACAGGAGAACTTTC TGGTAAGCATTTGGCTAACTTTTTTTTTTTTGAGATGGAGTCTTGCTGTGTCGCCTAGGC TGGAGTGCAGTGGCGTGATCTTGGCTCACTGCAGCCTCCACCTCCCGGGTTCAATCAATT CTCCTACCTCAACTTCCTGAGTAGCTGGGATTACAGGCGCCCGCCACCACACCCGGCTCA TTTTTGTACTTTTAGTAGAGACACAGTTTTGCCATGTTGGCCAGGCTGGTCTTGAATTCC TCAGCTCAGGTGATATGCCTGCCTTGGCCTCTCAAAGTGCTGGGATTACAGGCGTGAGCC ACTGTGCCCGGCCTTGGCTAACTTTTCAAAATTAAAGATTTTGACTTGTTACAGTCATGT GACATTTTTTTCTTTCTGTTTGGTGAGTTTTTGATAATTTATATCTCTCAAAGTGGAGAC TTTAAAAAAGACTCATCTGTGTGCCGTGTTCACTGCCTGGTATCTTAGTGTGGACCGAAG CCTAAGGACCCTGAAAACAGCTGCAGATGAAGATGGCAAGCACCCGCTGCAAGCTGGCCA GGTACCTGGAGGACCTGGAGGATGTGGACTTGAAGAAATTTAAGATGCACTTAGAGGACT ATCCTCCCCAGAAGGGCTGCATCCCCCTCCCGAGGGGTCAGACAGAGAAGGCAGACCATG TGGATCTAGCCACGCTAATGATCGACTTCAATGGGGAGGAGAAGGCGTGGGCCATGGCCG TGTGGATCTTCGCTGCGATCAACAGGAGAGACCTTTATGAGAAAGCAAAAAGAGATGAGC CGAAGTGGGGTTCAGATAATGCACGTGTTTCGAATCCCACTGTGATATGCCAGGAAGACA GCATTGAAGAGGAGTGGATGGGTTTACTGGAGTACCTTTCGAGAATCTCTATTTGTAAAA TGAAGAAAGATTACCGTAAGAAGTACAGAAAGTACGTGAGAAGCAGATTCCAGTGCATTG AAGACAGGAATGCCCGTCTGGGTGAGAGTGTGAGCCTCAACAAACGCTACACACGACTGC GTCTCATCAAGGAGCACCGGAGCCAGCAGGAGAGGGAGCAGGAGCTTCTGGCCATCGGCA AGACCAAGACGTGTGAGAGCCCCGTGAGTCCCATTAAGATGGAGTTGCTGTTTGACCCCG ATGATGAGCATTCTGAGCCTGTGCACACCGTGGTGTTCCAGGGGGCGGCAGGGATTGGGA AAACAATCCTGGCCAGGAAGATGATGTTGGACTGGGCGTCGGGGACACTCTACCAAGACA GGTTTGACTATCTGTTCTATATCCACTGTCGGGAGGTGAGCCTTGTGACACAGAGGAGCC TGGGGGACCTGATCATGAGCTGCTGCCCCGACCCAAACCCACCCATCCACAAGATCGTGA GAAAACCCTCCAGAATCCTCTTCCTCATGGACGGCTTCGATGAGCTGCAAGGTGCCTTTG ACGAGCACATAGGACCGCTCTGCACTGACTGGCAGAAGGCCGAGCGGGGAGACATTCTCC TGAGCAGCCTCATCAGAAAGAAGCTGCTTCCCGAGGCCTCTCTGCTCATCACCACGAGAC CTGTGGCCCTGGAGAAACTGCAGCACTTGCTGGACCATCCTCGGCATGTGGAGATCCTGG GTTTCTCCGAGGCCAAAAGGAAAGAGTACTTCTTCAAGTACTTCTCTGATGAGGCCCAAG CCAGGGCAGCCTTCAGTCTGATTCAGGAGAACGAGGTCCTCTTCACCATGTGCTTCATCC CCCTGGTCTGCTGGATCGTGTGCACTGGACTGAAACAGCAGATGGAGAGTGGCAAGAGCC TTGCCCAGACATCCAAGACCACCACCGCGGTGTACGTCTTCTTCCTTTCCAGTTTGCTGC AGCCCCGGGGAGGGAGCCAGGAGCACGGCCTCTGCGCCCACCTCTGGGGGCTCTGCTCTT TGGCTGCAGATGGAATCTGGAACCAGAAAATCCTGTTTGAGGAGTCCGACCTCAGGAATC ATGGACTGCAGAAGGCGGATGTGTCTGCTTTCCTGAGGATGAACCTGTTCCAAAAGGAAG TGGACTGCGAGAAGTTCTACAGCTTCATCCACATGACTTTCCAGGAGTTCTTTGCCGCCA TGTACTACCTGCTGGAAGAGGAAAAGGAAGGAAGGACGAACGTTCCAGGGAGTCGTTTGA AGCTTCCCAGCCGAGACGTGACAGTCCTTCTGGAAAACTATGGCAAATTCGAAAAGGGGT ATTTGATTTTTGTTGTACGTTTCCTCTTTGGCCTGGTAAACCAGGAGAGGACCTCCTACT TGGAGAAGAAATTAAGTTGCAAGATCTCTCAGCAAATCAGGCTGGAGCTGCTGAAATGGA TTGAAGTGAAAGCCAAAGCTAAAAAGCTGCAGATCCAGCCCAGCCAGCTGGAATTGTTCT ACTGTTTGTACGAGATGCAGGAGGAGGACTTCGTGCAAAGGGCCATGGACTATTTCCCCA AGATTGAGATCAATCTCTCCACCAGAATGGACCACATGGTTTCTTCCTTTTGCATTGAGA ACTGTCATCGGGTGGAGTCACTGTCCCTGGGGTTTCTCCATAACATGCCCAAGGAGGAAG AGGAGGAGGAAAAGGAAGGCCGACACCTTGATATGGTGCAGTGTGTCCTCCCAAGCTCCT CTCATGCTGCCTGTTCTCATGGATTGGTGAACAGCCACCTCACTTCCAGTTTTTGCCGGG GCCTCTTTTCAGTTCTGAGCACCAGCCAGAGTCTAACTGAATTGGACCTCAGTGACAATT CTCTGGGGGACCCAGGGATGAGAGTGTTGTGTGAAACGCTCCAGCATCCTGGCTGTAACA TTCGGAGATTGTGGTTGGGGCGCTGTGGCCTCTCGCATGAGTGCTGCTTCGACATCTCCT TGGTCCTCAGCAGCAACCAGAAGCTGGTGGAGCTGGACCTGAGTGGACAACGCCCTCGGTG ACTTCGGAATCAGACTTCTGTGTGTGGGACTGAAGCACCTGTTGTGCAATCTGAAGAAGC TCTGGTTGGTCAGCTGCTGCCTCCACATCAGCATGTTGTCAGGATCTTGCATCAGTATTGA GCACCAGCCATTCCCTGACCAGACTCTATGTGGGGGAGAATGCCTTGGGAGACTCAGGAG TCGCAATTTTATGTGAAAAAGCCAAGAATCCACAGTGTAACCTGCAGAAACTGGGGTTGG TGAATTCTGGCCTTACGTCAGTCTGTTGTTCAGCTTTGTCCTCGGTACTCAGCACTAATC AGAATCTCACGCACCTTTACCTGCGAGGCAACACTTCCGGAGACAAGGGGATCAAACTAC TCTGTGAGGGACTCTTGCACCCCGACTGCAAGCTTCAGGTGTTGGAATTAGACAACTGCA ACCTCACGTCACACTGCTGCTGGGATCTTTCCACACTTCTGACCTCCAGCCAGAGCCTGC GAAAGCTGAGCCTGGGCAACAATGACCTGGGCGACCTGGGGGTCATGATGTTCTGTGAAG TGCTGAAACAGCAGAGCTGCCTCCTGCAGAACCTGGGGTTGTCTGAAATGTATTTCAATT ATGAGACAAAAAGTGCGTTAGAAACACTTCAAGAAGAAAAGCCTGAGCTGACCGTCGTCT TTGAGCCTTCTTGGTAGGAGTGGAAACGGGGCTGCCAGACGCCAGTGTTCTCCGGTCCCT CCAGCTGGGGGCCCTCAGGTGGAGAGAGCTGCGATCCATCCAGGCCAAGACCACAGCTCT GTGATCCTTCCGGTGGAGTGTCGGAGAAGAGAGCTTGCCGACGATGCCTTCCTGTGCAGA GCTTGGGCATCTCCTTTACGCCAGGGTGAGGAAGACACCAGGACAATGACAGCATCGGGT GTTGTTGTCATCACAGCGCCTCAGTTAGAGGATGTTCCTCTTGGTGACCTCATGTAATTA GCTCATTCAATAAAGCACTTTCTTTATTTT (SEQ ID NO: 56)

[0374] As used herein, the term "NME8" refers to the gene encoding thioredoxin domain-containing protein 3. The terms "NME8" and "thioredoxin domain-containing protein 3" include wild-type forms of the NME8 gene, as well as variants of the wild-type NME8 (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type NME8 nucleic acid sequence (e.g., SEQ ID NO:57, ENA Accession No. AF202051). SEQ ID NO:57 is the wild-type gene sequence encoding the NME8 protein and is shown below. CGGCCACAACGAGGGAGCCGATTTAGATCCTCTGGGCCTGTTCCTTCCTTTTCTTTAAAC GTCCCAGTCTAGCTTAGAGGAGGACCTGTTTTGTTAGATAAAATGGCAAGCAAAAAACGAG AAGTCCAGTTACAGACAGTCATCAATAATCAAAGCCTGTGGGATGAGATGTTGCAGAACA AAGGCTTAACAGTGATTGATGTTTACCAAGCCTGGTGTGGACCTTGCAGAGCAATGCAAC CTTTATTCAGAAAATTGAAAAATGAACTGAACGAAGACGAAATTCTGCATTTTGCTGTCG CAGAAGCTGACAACATTGTGACTTTGCAGCCATTTAGAGATAAATGTGAACCTGTTTTTC TCTTTAGTGTTAATGGCAAAATTATCGAAAAGATTCAGGGTGCAAATGCACCGCTTGTTA ATAAAAAAGTTATTAATTTGATCGATGAGGAGAGAAAAATTGCAGCAGGTGAAATGGCTC GACCTCAGTATCCTGAAATTCCATTAGTAGACTCAGATTCAGAAGTTAGTGAAGAATCAC CATGTGAAAGTGTTCAGGAATTATACAGTATTGCTATTATCAAACCGGATGCTGTGATTA GTAAAAAAGTTCTAGAAATTAAAAAGAAAAATTACCAAAGCTGGATTTATTATAGAAGCAG AGCATAAGACAGTGCTCACTGAAGAACAAGTTGTCAACTTCTATAGTCGAATAGCAGACC AGTGTGACTTCGAAGAGTTTGTCTCTTTTATGACAAGTGGCTTAAGCTATATTCTAGTTG TATCTCAAGGAAGTAAACACAATCCTCCCTCTGAAGAAACCGAACCACAGACTGACACCG AACCTAACGAACGATCTGAGGATCAACCTGAGGTCGAAGCCCAGGTTACACCTGGAATGA TGAAGAACAAACAAGACAGTTTACAAGAATATCTGGAAAGACAACATTTAGCTCAGCTCT GTGACATTGAAGAGGATGCAGCTAAGTTCATGGATGCTTTCTTCCCCGATT TTAAAAAAATGAAAAGCATGAAAATTAGAAAAGACATTGGCATTACTTCGACCAAATCTCT TTCATGAAAGGAAAGATGATGTTTTGCGTATTATTAAAGATGAAGACTTCAAAATACTGG AGCAAAGACAAGTAGTATTATCGGAAGAAGAAGCACAAGCACTGTGCAAGGAATATGAAA ATGAAGACTATTTTAATAAACTTATAGAAAACATGACCAGTGGTCCATCTCTAGCCCTTG TTTTATTGAGAGACAATGGCTTGCAATACTGGAAACAATTACTGGGACCAAGAACTGTTG AAGAAGCCATTGAATATTTTCCAGAGAGTTTATGTGCACAGTTTGCGATGGACAGTTTGC CGGTCAACCAGTTGTATGGCAGCGATTCATTAGAAACCGCTGAAAGGGAAATACAGCATT TCTTTCCTCTTCAAAGCACTTTAGGCTTGATTAAACCTCATGCAACAAGTGAACAAAGAG AGCAGATCCTGAAGATAGTTAAGGAGGCTGGATTTGATCTGACACAGGTGAAGAAAATGT TCCTAACTCCTGAGCAAATAGAGAAAATTTATCCAAAAGTAACAGGAAAAGACTTTTATA AAGATTTATTGGAAATGTTATCTGTGGGTCCATCTATGGTCATGATTCTGACCAAGTGGA ATGCTGTTGCAGAATGGAGACGATTGATGGGCCCAACAGACCCAGAAGAAGCAAAATTAC TTTCCCCTGACTCCATCCGAGCCCAGTTTGGAATAAGTAAATTGAAAAACATTGTCCATG GAGCATCTAACGCCTATGAAGCAAAAGAGGTTGTTAATAGACTCTTTGAGGATCCTGAGG AAAACTAAAGTATATACTGTGAAAACTTTGAGAAGATAATACATATGTTCACGTCAATAT ACAACCATTTGGCACAGCTTCCTGGGAGGAATAATAAGAAAAACATGCTTTGGAGGAAAA CTCAAGATACAAAAATGAATGGCTATGCATAATAACAATAAAAATGTATTCCCCAAAC (SEQ ID NO: 57)

[0375] As used herein, the term "NOS2" refers to the gene encoding inducible nitric oxide synthase. The terms "NOS2" and "inducible nitric oxide synthase" include wild-type forms of the NOS2 gene, as well as variants of the wild-type NOS2 (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type NOS2 nucleic acid sequence (e.g., SEQ ID NO:58, ENA Accession No. L24553). SEQ ID NO:58 is the wild-type gene sequence encoding the NOS2 protein and is shown below. AAGCCCCACAGTGAAGAACATCTGAGCTCAAATCCAGATAAGTGACATAAGTGACCTGCT TTGTAAAGCCATAGAGATGGCCTGTCCTTGGAAATTTCTGTTCAAGACCAAATTCCACCA GTATGCAATGAATGGGGAAAAAAGACATCAACAACAATGTGGAGAAAGCCCCCTGTGCCAC CTCCAGTCCAGTGACACAGGATGACCTTCAGTATCACAACCTCAGCAAGCAGCAGAATGA GTCCCCGCAGCCCCTCGTGGAGACGGGAAAGAAGTCTCCAGAATCTCTGGTCAAGCTGGA TGCAACCCCATTGTCCTCCCCACGGCATGTGAGGATCAAAAACTGGGGCAGCGGGATGAC TTTCCAAGACACACTTCACCATAAGGCCAAAGGGATTTTAACTTGCAGGTCCAAATCTTG CCTGGGGTCCATTATGACTCCCAAAAGTTTGACCAGAGGACCCAGGGACAAGCCTACCCC TCCAGATGAGCTTCTACCTCAAGCTATCGAATTTGTCAACCAATATTACGGCTCCTTCAA AGAGGCAAAAATAGAGGAACATCTGGCCAGGGTGGAAGCGGTAACAAAGGAGATAGAAAC AACAGGAACCTACCAACTGACGGGAGATGAGCTCATCTTCGCCACCAAGCAGGCCTGGCG CAATGCCCCACGCTGCATTGGGAGGATCCAGTGGTCCAACCTGCAGGTCTTCGATGCCCG CAGCTGTTCCACTGCCCGGGAAATGTTTGAACACATCTGCAGACACGTGCGTTACTCCAC CAACAATGGCAACATCAGGTCGGCCATCACCGTGTTCCCCCAGCGGAGTGATGGCAAGCA CGACTTCCGGGTGTGGAATGCTCAGCTCATCCGCTATGCTGGCTACCAGATGCCAGATGG CAGCATCAGAGGGGACCCTGCCAACGTGGAATTCACTCAGCTGTGCATCGACCTGGGCTG GAAGCCCAAGTACGGCCGCTTCGATGTGGTCCCCCTGGTCCTGCAGGCCAATGGCCGTGA CCCTGAGCTCTTCGAAATCCCACCTGACCTTGTGCTTGAGGTGGCCATGGAACATCCCAA ATACGAGTGGTTTCGGGAACTGGAGCTAAAGTGGTACGCCCTGCCTGCAGTGGCCAACAT GCTGCTTGAGGTGGGCGGCCTGGAGTTCCCAGGGTGCCCCTTCAATGGCTGGTACATGGG CACAGAGATCGGAGTCCGGGACTTCTGTGACGTCCAGCGCTACAACATCCTGGAGGAAGT GGGCAGGAGAATGGGCCTGGAAACGCACAAGCTGGCCTCGCTCTGGAAAGACCAGGCTGT CGTTGAGATCAACATTGCTGTGCTCCATAGTTTCCAGAAGCAGAATGTGACCATCATGGA CCACCACTCGGCTGCAGAATCCTTCATGAAGTACATGCAGAATGAATACCGGTCCCGTGG GGGCTGCCCGGCAGACTGGATTTGGCTGGTCCCTCCCATGTCTGGGAGCATCACCCCCGT GTTTCACCAGGAGATGCTGAACTACGTCCTGTCCCCTTTCTACTACTATCAGGTAGAGGC CTGGAAAACCCATGTCTGGCAGGACGAGAAGCGGAGACCCAAGAGAAGAGAGATTCCATT GAAAGTCTTGGTCAAAGCTGTGCTCTTTGCCTGTATGCTGATGCGCAAGACAATGGCGTC CCGAGTCAGAGTCACCATCCTCTTTGCGACAGAGACAGGAAAATCAGAGGCGCTGGCCTG GGACCTGGGGGCCTTATTCAGCTGTGCCTTCAACCCCAAGGTTGTCTGCATGGATAAGTA CAGGCTGAGCTGCCTGGAGGAGGAACGGCTGCTGTTGGTGGTGACCAGTACGTTTGGCAA TGGAGACTGCCCTGGCAATGGAGAGAAACTGAAGAAATCGCTCTTCATGCTGAAAGAGCT CAACAACAAATTCAGGTACGCTGTGTTTGGCCTCGGCTCCAGCATGTACCCTCGGTTCTG CGCCTTTGCTCATGACATTGATCAGAAGCTGTCCCACCTGGGGGCCTCTCAGCTCACCCC GATGGGAGAAGGGGATGAGCTCAGTGGGCAGGAGGACGCCTTCCGCAGCTGGGCCGTGCA AACCTTCAAGGCAGCCTGTGAGACGTTTGATGTCCGAGGCAAACAGCACATTCAGATCCC CAAGCTCTACACCTCCAATGTGACCTGGGACCCGCACCACTACAGGCTCGTGCAGGACTC ACAGCCTTTGGACCTCAGCAAAGCCCTCAGCAGCATGCATGCCAAGAACGTGTTCACCAT GAGGCTCAAATCTCGGCAGAATCTACAAAGTCCGACATCCAGCCGTGCCACCATCCTGGT GGAACTCTCCTGTGAGGATGGCCAAGGCCTGAACTACCTGCCGGGGGAGCACCTTGGGGT TTGCCCAGGCAACCAGCCGGCCCTGGTCCAAGGCATCCTGGAGCGAGTGGTGGATGGCCC CACACCCCACCAGACAGTGCGCCTGGAGGCCCTGGATGAGAGTGGCAGCTACTGGGTCAG TGACAAGAGGCTGCCCCCCTGCTCACTCAGCCAGGCCCTCACCTACTTCCTGGACATCAC CACACCCCCAACCCAGCTGCTGCTCCAAAAGCTGGCCCAGGTGGCCACAGAAGAGCCTGA GAGACAGAGGCTGGAGGCCCTGTGCCAGCCCTCAGAGTACAGCAAGTGGAAGTTCACCAA CAGCCCCACATTCCTGGAGGTGCTAGAGGAGTTCCCGTCCCTGCGGGTGTCTGCTGGCTT CCTGCTTTCCCAGCTCCCCATTCTGAAGCCCAGGTTCTACTCCATCAGCTCCTCCCGGGA TCACACGCCCACGGAGATCCACCTGACTGTGGCCGTGGTCACCTACCACACCCGAGATGG CCAGGGTCCCCTGCACCACGGCGTCTGCAGCACATGGCTCAACAGCCTGAAGCCCCAAGA CCCAGTGCCCTGCTTTGTGCGGAATGCCAGCGGCTTCCACCTCCCCGAGGATCCCTCCCA TCCTTGCATCCTCATCGGGCCTGGCACAGGCATCGCGCCCTTCCGCAGTTTCTGGCAGCA ACGGCTCCATGACTCCCAGCACAAGGGAGTGCGGGGAGGCCGCATGACCTTGGTGTTTGG GTGCCGCCGCCCAGATGAGGACCACATCTACCAGGAGGAGATGCTGGAGATGGCCCAGAA GGGGGTGCTGCATGCGGTGCACACAGCCTATTCCCGCCTGCCTGGCAAGCCCAAGGTCTA TGTTCAGGACATCCTGCGGCAGCAGCTGGCCAGCGAGGTGCTCCGTGTGCTCCACAAGGA GCCAGGCCACCTCTATGTTTGCGGGGATGTGCGCATGGCCCGGGACGTGGCCCACACCCT GAAGCAGCTGGTGGCTGCCAAGCTGAAATTGAATGAGGAGCAGGTCGAGGACTATTTCTT TCAGCTCAAGAGCCAGAAGCGCTATCACGAAGATATCTTTGGTGCTGTATTTCCTTACGA GGCGAAGAAGGACAGGGTGGCGGTGCAGCCCAGCAGCCTGGAGATGTCAGCGCTCTGAGG GCCTACAGGAGGGGTTAAAGCTGCCGGCACAGAACTTAAGGATGGAGCCAGCTCT (SEQ ID NO: 58)

[0376] As used herein, the term "PICALM" refers to a gene encoding a phosphatidylinositol-binding clathrin assembly protein. The terms "PICALM" and "phosphatidylinositol-binding clathrin assembly protein" include wild-type forms of the PICALM gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type PICALM. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type PICALM nucleic acid sequence (e.g., SEQ ID NO: 59, ENA Accession No. U45976). SEQ ID NO: 59 is the wild-type gene sequence encoding the PICALM protein and is shown below. GCGCGGCCCCGAACCGCCGCCAGGCCGGCACGGGGGAAGGAGCCGGTGGGGTAGGGGGT GCGGTGGGGGGTGGGGACCCTCCGGCTCTTGGGGGTCCCAGTCCCCGCCGGCTGCTGAGC GGGTGGGGTGGTGGAGGAGCTGCAGAGATGTCCGGCCAGAGCCTGACGGACCGAATCACT GCCGCCCAGCACAGTGTCACCGGCTCTGCCGTATCCAAGACAGTATGCAAGGCCACGACC CACGAGATCATGGGGCCCAAGAAAAAGCACCTGGACTACTTAATTCAGTGCACAAATGAG ATGAATGTGAACATCCCACAGTTGGCAGACAGTTTATTTGAAAGAACTACTAATAGTAGT TGGGTGGTGGTCTTCAAATCTCTCATTACAACTCATCATTTGATGGTGTATGGAAATGAG CGTTTTATTCAGTATTTGGCTTCAAGAAACACGTTGTTTAACTTAAGCAATTTTTTGGAT AAAAGTGGATTGCAAGGATATGACATGTCTACATTTATTAGGCGGTATAGTAGATATTTA AATGAGAAAGCAGTTTCATACAGACAAGTTGCATTTGATTTCACAAAAGTGAAGAGAGGG GCTGATGGAGTTATGAGAACAATGAACACAGAAAAACTCCTAAAAACTGTACCAATTATT CAGAATCAAATGGATGCACTTCTTGATTTTAATGTTAATAGCAATGAACTTACAAATGGG GTAATAAATGCTGCCTTCATGCTCCTGTTCAAAGATGCCATTAGACTGTTTGCAGCATAC CATGAAGGAATTATTAATTTGTTGGAAAAATATTTTGATATGAAAAAGAACCAATGCAAA GAAGGTCTTGACATCTATAAGAAGTTCCTAACTAGGATGACAAGAATCTCAGAGTTCCTC AAAGTTGCAGAGCAAGTTGGAATTGACAGAGGTGATATACCACAGACCTTTCACAGGCCCCT AGCAGTCTTCTTGATGCTTTGGAACAACATTTAGCTTCCTTGGAAGGAAAGAAAATCAAA GATTCTACAGCTGCAAGCAGGGCAACTACACTTTCCAATGCAGTGTCTTCCCCTGGCAAGC ACTGGTCTATCTCTGACCAAAGTGGATGAAAGGGAAAAGCAGGCAGCATTAGAGGAAGAA CAGGCACGTTTGAAAGCTTTAAAGGAACAGCGCCTAAAAGAACTTGCAAAGAAACCTCAT ACCTCTTTAACAACTGCAGCCTCTCCTGTATCCACCTCAGCAGGAGGGATAATGACTGCA CCAGCCATTGACATATTTTCTACCCCTAGTTCTTCTAACAGCACATCAAAGCTGCCCAAT GATCTGCTTGATTTGCAGCAGCCAACTTTTCACCCATCTGTACATCCTATGTCAACTGCT TCTCAGGTAGCAAGTACATGGGGAGATCCTTTCTCTGCTACTGTAGATGCTGTTGATGAT GCCATTCCAAGCTTAAATCCTTTCCTCACAAAAAGTAGTGGTGATGTTCACCTTTCCATT TCTTCAGATGTATCTACTTTTACTACTAGGACACCTACTCATGAAATGTTTGTTGGATTC ACTCCTTCTCCAGTTGCACAGCCACACCCTTCAGCTGGCCTTAATGTTGACTTTGAATCT GTGTTTGGAAATAAATCTACAAATGTTATTGTAGATTCTGGGGGCTTTGATGAACTAGGT GGACTTCTCAAACCAACAGTGGCCTCTCAGAACCAGAACCTTCCTGTTGCCAAACTCCCA CCTAGCAAGTTAGTATCTGATGACTTGGATTCATCTTTAGCCAACCTTGTGGGCAATCTT GGCATCGGAAATGGAACCACTAAGAATGATGTAAATTGGAGTCAACCAGGTGAAAAGAAG TTAACTGGGGGATCTAACTGCGAACCAAAGGTTGCACCAACAACCGCTTGGAATGCTGCA ACAATGGCACCCCCTGTAATGGCCTATCCTGCTACTACACCAACAGGCATGATAGGATAT GGAATTCCTCCACAAATGGGAAGTGTTCCTGTAATGACGCAACCAACCTTAATATACAGC CAGCCTGTCATGAGACCTCCAAACCCCTTTGGCCCTGTATCAGGAGCACAGATACAGTTT ATGTAACTTGATGGAAGAAAATGGAATTACTCCAAAAAGACAAGTGCTCAAGCAGCAAAA TCCTTACTTCCAGCAAAAATCCAAACTGCTGTCTCTTAAATCTCTTAAACTCTCTTCTTCC ATTAGGATGCTACAAGTANCTCAGTGAAGGCCCATGAAGGGAATTGGGGACTAGTTTATA GGGNGAACGTATTCATTACAGTTTATAAAGGCCAGGATTGGNTTGGATTTTAGGATTANG TTC (SEQ ID NO:59)

[0377] As used herein, the term "PILRA" refers to the gene encoding the immunoglobin-like type 2 receptor alpha. The terms "PILRA" and "anti-immunoglobin-like type 2 receptor alpha" include wild-type forms of the PILRA gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type PILRA. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type PILRA nucleic acid sequence (e.g., SEQ ID NO: 60, NCBI Reference Sequence: NM_013439.2). SEQ ID NO: 60 is the wild-type gene sequence encoding the PILRA protein and is shown below. (SEQ ID NO:60)

[0378] As used herein, the term "PLCG2" refers to the gene encoding 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2. The terms "PLCG2" and "1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2" include wild-type forms of the PLCG2 gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type PLCG2. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type PLCG2 nucleic acid sequence (e.g., SEQ ID NO: 61, ENA Accession No. M37238). SEQ ID NO: 61 is the wild-type gene sequence encoding the PLCG2 protein and is shown below. GAATTCGGCGCTGAGTGACCCGAGTCGGGACGCGGGCTGCGCGCGGGGACCCCGGAGCC CAAACCCGGGGCAGGCGGGCAGCTGTGCCCGGGCGGCACGGCCAGCTTCCTGATTTCTCC CGATTCCTTCCTTCTCCCTGGAGCGGCCGACAATGTCCACCACGGTCAATGTAGATTCCC TTGCGGAATATGAGAAGAGCCAGATCAAGAGAGCCCTGGAGCTGGGGACGGTGATGACTG TGTTCAGCTTCCGCAAGTCCACCCCCGAGCGGAGAACCGTCCAGGTGATCATGGAGACGC GGCAGGTGGCCTGGAGCAAGACCGCCGACAAGATCGAGGGCTTCTTGGATATCATGGAAA TAAAAGAAATCCGCCCAGGGAAGAACTCCAAAGATTTCGAGCGAGCAAAAGCAGTTCGCC AGAAAGAAGACTGCTGCTTCACCATCCTATATGGCACTCAGTTCGTCCTCAGCACGCTCA GCTTGGCAGCTGACTCTAAAGAGGATGCAGTTAACTGGCTCTCTGGCTTGAAAATCTTAC ACCAGGAAGCGATGAATGCGTCCACGCCCACCATTATCGAGAGTTGGCTGAGAAAGCAGA TATATTCTGTGGATCAAACCAGAAGAAACAGCATCAGTCTCCGAGAGTTGAAGACCATCT TGCCCCTGATCAACTTTAAAGTGAGCAGTGCCAAGTTCCTTAAAAGATAAGTTTGTGGAAA TAGGAGCACACAAAGATGAGCTCAGCTTTGAACAGTTCCATCTCTTCTATAAAAAACTTA TGTTTGAACAGCAAAAATCGATTCTCGATGAATTCAAAAGGATTCGTCCGTGTTCATCC TGGGGAACACTGACAGGCCGGATGCCTCTGCTGTTTACCTGCATGACTTCCAGAGGTTTC TCATACATGAACAGCAGGAGCATTGGGCTCAGGATCTGAACAAAGTCCGTGAGGCGGATGA CAAAGTTCATTGATGACACCATGCGTGAAACTGCTGAGCCTTTCTTGTTTGTGGATGAGT TCCTCACGTACCTGTTTTCACGAGAAAACAGCATCTGGGATGAGAAGTATGACGCGGTGG ACATGCAGGACATGAACAACCCCCTGTCTATTACTGGATCTCCTCGTCACATAAACAGGT ACCTTACAGGTGACCAGCTGCGGAGCGAGTCGTCCCCAGAAGCTTACATCCGCTGCCTGC GCATGGGCTGTCGCTGCATTGAACTGGACTGCTGGGACGGGCCCGATGGGAAGCCGGTCA TCTACCATGGCTGGACGCGGACTACCAAGATCAAGTTTGATGACGTCGTGCAGGCCATCA AAGACCACGCCTTTGTTACCTCGAGCTTCCCAGTGATCCTGTCCATCGAGGAGCACTGCA GCGTGGAGCAACAGCGTCACATGGCCAAGGCCTTCAAGGAAGTATTTGGCGACCTGCTGT TGACGAAGCCCACGGAGGCCAGTGCTGACCAGCTGCCCTCGCCCAGCCAGCTGCGGGAGA AGATCATCATCAAGCATAAGAAGCTGGGCCCCCGAGGCGATGTGGATGTCAACATGGAGG ACAAGAAGGACGAACACAAGCAACAGGGGGAGCTGTACATGTGGGATTCCATTGACCAGA AATGGACTCGGCACTACTGCGCCATTGCTGATGCCAAGCTGTCCTTCAGTGATGACATTG AACAGACTATGGAGGAGGAAGTGCCCCAGGATATACCCCCTACAGAACTACATTTTGGGG AGAAATGGTTCCACAAGAAGGTGGAGAAGAGGACGAGTGCCGAGAAGTTGCTGCAGGAAT ACTGCATGGAGACGGGGGGCAAGGATGGCACCTTCCTGGTTCGGGAGAGCGAGACCTTCC CCAATGACTACACCCTGTCCTTCTGGCGGTCAGGCCGGGTCCAGCACTGCCGGATCCGCT CCACCATGGAGGGCGGGACCCTGAAATACTACTTGACTGACAACCTGAGGTTCAGGAGGA TGTATGCCCTCATCCAGCACTACCGCGAGACGCACCTGCCGTGCGCCGAGTTCGAGCTGC GGCTCACGGACCCTGTGCCCAACCCCAACCCCCACGAGTCCAAGCCGTGGTACTATGACA GCCTGAGCCGCGGAGAGGCAGAGGACATGCTGATGAGGATTCCCCGGGACGGGGCCTTCC TGATCCGGAAGCGAGAGGGGAGCGACTCCTATGCCATCACCTTCAGGGCTAGGGGCAAGG TAAAGCATTGTCGCATCAACCGGGACGGCCGGCACTTTGTGCTGGGGACCTCCGCCTATT TTGAGAGTCTGGTGGAGCTCGTCAGTTACTACGAGAAGCATTCACTCTACCGAAAGATGA GACTGCGCTACCCCGTGACCCCCGAGCTCCTGGAGCGCTACAATACGGAAAGAGATATAA ACTCCCTCTACGACGTCAGCAGAATGTATGTGGATCCCAGTGAAATCAATCCGTCCATGC CTCAGAGAACCGTGAAAGCTCTGTATGACTACAAAGCCAAGCGAAGCGATGAGCTGAGCT TCTGCCGTGGTGCCCTCATCCACAATGTCTCCAAGGAGCCCGGGGGCTGGTGGAAAGGAG ACTATGGAACCAGGATCCAGCAGTACTTCCCATCCAACTACGTCGAGGACATCTCAACTG CAGACTTCGAGGAGCTAGAAAAGCAGATTATTGAAGACAATCCCTTAGGGTCTCTTTGCA GAGGAATATTGGACCTCAATACCTATAACGTCGTGAAAGCCCCTCAGGGAAAAAACCAGA AGTCCTTTGTCTTCATCCTGGAGCCCAAGGAGCAGGGCGATCCTCCGGTGGAGTTTGCCA CAGACAGGGTGGAGGAGCTCTTTGAGTGGTTTCAGAGCATCCGAGAGATCACGTGGAAGA TTGACAGCAAGGAGAACAACATGAAGTACTGGGAGAAGAACCAGTCCATCGCCATCGAGC TCTCTGACCTGGTTGTCTACTGCAAACCAACCAGCAAAACCAAGGACAACTTAGAAAATC CTGACTTCCGAGAAATCCGCTCCTTTGTGGAGACGAAGGCTGACAGCATCATCAGACAGA AGCCCGTCGACCTCCTGAAGTACAATCAAAAGGGCCTGACCCGCGTCTACCCAAAGGGAC AAAGAGTTGACTCTTCAAACTACGACCCCTTCCGCCTCTGGCTGTGCGGTTCTCAGATGG TGGCACTCAATTTCCAGACGGCAGATAAGTACATGCAGATGAATCACGCATTGTTTTCTC TCAACGGGCGCACGGGCTACGTTCTGCAGCCTGAGAGCATGAGGACAGAGAAATATGACC CGATGCCACCCGAGTCCCAGAGGAAGATCCTGATGACGCTGACAGTCAAGGTTCTCGGTG CTCGCCATCTCCCCAAACTTGGACGAAGTATTGCCTGTCCCTTTGTAGAAGTGGAGATCT GTGGAGCCGAGTATGGCAACAACAAGTTCAAGACGACGGTTGTGAATGATAATGGCCTCA GCCCTATCTGGGCTCCAACACAGGAGAAGGTGACATTTGAAATTTATGACCCAAACCTGG CATTTCTGCGCTTTGTGGTTTATGAAGAAGATATGTTCAGCGATCCCAACTTTCTTGCTC ATGCCACTTACCCCATTAAAGCAGTCAAATCAGGATTCAGGTCCGTTCCTCTGAAGAATG GGTACAGCGAGGACATAGAGCTGGCTTCCCTCCTGGTTTTCTGTGAGATGCGGCCAGTCC TGGAGAGCGAAGAGGAACTTTACTCCTCCTGTCGCCAGCTGAGGAGGCGGCAAGAAGAAC TGAACAACCAGCTCTTTCTGTATGACACACACCAGAACTTGCGCAATGCCAACCGGGATG CCCTGGTTAAAGAGTTCAGTGTTAATGAGAACCACTCCAGCTGTACCAGGAGAAATGCAA CAAGAGGTTAAGAGAGAAGAGAGTCAGCAACAGCAAGTTTTACTCATAGAAGCTGGGGTA TGTGTGTAAGGGTATTGTGTGTGTGCGCATGTGTGTTTGCATGTAGGAGAACGTGCCCTA TTCACACTCTGGGAAGACGCTAATCTGTGACATCTTTTCTTCAAGCCTGCCATCAAGGAC ATTTCTTAAGACCCAACTGGCATGAGTTGGGGTAATTTCCTATTATTTTCATCTTGGACA ACTTCTAACTTATATCTTTATAGAGGATTCCCCAAAATGTGCTCCTCATTTTTGGCCTCT CATGTTCCAAACCTCATTGAATAAAAAGCAATGAAAACCTTG (SEQ ID NO: 61)

[0379] As used herein, the term "PTK2B" refers to the gene encoding protein tyrosine kinase 2 beta. The terms "PTK2B" and "protein tyrosine kinase 2 beta" include wild-type forms of the PTK2B gene, as well as variants of the wild-type PTK2B (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type PTK2B nucleic acid sequence (e.g., SEQ ID NO: 62, ENA Accession No. U33284). SEQ ID NO: 62 is the wild-type gene sequence encoding the PTK2B protein and is shown below. CGGTACAGGTAAGTCGGCCGGGCAGGTAGGGGTGCCCGAGGAGTAGTCGCTGGAGTCCGC GCCTCCCTGGGACTGCAATGTGCCGGTCTTAGCTGCTGCCTGAGAGGATGTCTGGGGTGT CCGAGCCCCTGAGCCGAGTAAAGTTGGGCACATTACGCCGGCCTGAAGGCCCTGCAGAGC CCATGGTGGTGGTACCAGTAGATGTGGAAAAGGAGGACGTGCGTATCCTCAAGGTCTGCT TCTATAGCAACAGCTTCAATCCTGGGAAGAACTTCAAACTGGTCAAATGCACTGTCCAGA CGGAGATCCGGGAGATCATCACCTCCATCCTGCTGAGCGGGCGGATCGGGCCCAACATCC GGTTGGCTGAGTGCTATGGGCTGAGGCTGAAGCACATGAAGTCCGATGAGATCCACTGGC TGCACCCACAGATGACGGTGGGTGAGGTGCAGGACAAGTATGAGTGTCTGCACGTGGAAG CCGAGTGGAGGTATGACCTTCAAATCCGCTACTTGCCAGAAGACTTCATGGAGAGCCTGA AGGAGGACAGGACCAGCCACGCTGCTCTTATTTTTACCAACAGCTCGGAACGACTACATGCAGC GCTACGCCAGCAAGGTCAGCGAGGGCATGGCCCTGCAGCTGGGCTGCCTGGAGCTCAGGC GGTTCTTCAAGGATATGCCCCACAATGCACTTGACAAGAAGTCCAACTTCGAGCTCCTAG AAAAGGAAGTGGGGCTGGACTTGTTTTTCCCAAAGCAGATGCAGGAGAACTTAAAGCCCA AACAGTTCCGGAAGATGATCCAGCAGACCTTCCAGCAGTACGCCTCGCTCAGGGAGGAGG AGTGCGTCATGAAGTTCTTCAACACTCTCGCCGGCTTCGCCAACATCGACCAGGAGACCT ACCGCTGTGGAACTCATTCAAGGATGGAACATTACTGTGGACCTGGTCATTGGCCCTAAAG GGATCCGCCAGCTGACTAGTCAGGACGCAAAGCCCACCTGCCTGGCCGAGTTCAAGCAGA TCAGGTCCATCAGGTGCCTCCCGCTGGAGGAGGGCCAGGCAGTACTTCAGCTGGGCATTG AAGGTGCCCCCAGGCCTTGTCCATCAAACCTCATCCCTAGCAGAGGCTGAGAACATGG CTGACCTCATAGACGGCTACTGCCGGCTGCAGGGTGAGCACCAAGGCTCTCTCATCATCC ATCCTAGGAAAGATGGTGAGAAGCGGAACAGCCTGCCCAGATCCCCATGCTAAACCTGG AGGCCCGGCGGTCCCACCTCTCAGAGAGCTGCAGCATAGAGTCAGACATCTACGCAGAGA TTCCCGACGAAACCCTGCGAAGGCCCGGAGGTCCACAGTATGGCATTGCCCGTGAAGATG TGGTCCTGAATCGTATTCTTGGGGAAGGCTTTTTTGGGGAGGTCTATGAAGGTGTCTACA CAAATCACAAAGGGGAGAAAATCAATGTAGCTGTCAAGACCTGCAAGAAAGACTGCACTC TGGACAACAAGGAGAAGTTCATGAGCGAGGCAGTGATCATGAAGAACCTCGACCACCCGC ACATCGTGAAGCTGATCGGCATCATTGAAGAGGAGCCCACCTGGATCATCATGGAATTGT ATCCCTATGGGGAGCTGGGCCACTACCTGGAGCGGAACAAGAACTCCCTGAAGGTGCTCA CCCTCGTGCTGTACTCACTGCAGATATGCAAAGCCATGGCCTACCTGGAGAGCATCAACT GCGTGCACAGGGACATTGCTGTCCGGAACATCCTGGTGGCCTCCCCTGAGTGTGTGAAGC TGGGGGACTTTGGTCTTTCCCGGTACATTGAGGACGAGGACTATTACAAAGCCTCTGTGA CTCGTCTCCCCATCAAATGGATGTCCCCAGAGTCCATTAACTTCCGACGCTTCACGACAG CCAGTGACGTCTGGATGTTCGCCGTGTGCATGTGGGAGATCCTGAGCTTTGGGAAGCAGC CCTTCTTCTGGCTGGAGAACAAGGATGTCATCGGGGTGCTGGAGAAAGGAGACCGGCTGC CCAAGCCTGATCTCTGTCCACCGGTCCTTTATACCCTCATGACCCGCTGCTGGGACTACG ACCCCAGTGACCGGCCCCGCTTCACCGAGCTGGTGTGCAGCCTCAGTGACGTTTATCAGA TGGAGAAGGACATTGCCATGGAGCAAGAGAGGAATGCTCGCTACCGAACCCCCAAAATCT TGGAGCCCACAGCCTTCCAGGAACCCCCACCCAAGCCCAGCCGACCTAAGTACAGACCCC CTCCGCAAACCAACCTCCTGGCTCCAAAGCTGCAGTTCCAGGTTCCTGAGGGTCTGTTGTG CCAGCTCTCCTACGCTCACCAGCCCTATGGAGTATCCATCTCCCGTTAACTCACTGCACA CCCCACCTCTCCACCGGCACAATGTCTTCAAACGCCACAGCATGCGGGAGGAGGACTTCA TCCAACCCAGCAGCCGAGAAGAGGCCAGCAGCTGTGGGAGGCTGAAAAGGTCAAAATGC GGCAAATCCTGGACAAACAGCAGAAGCAGATGGTGGAGGGACTACCAGTGGCTCAGGCAGG AGGAGAAGTCCCTGGACCCCCATGGTTTATATGATAAGTCCCCATTGACGCCAGAGA AGGAGGTCGGCTACCTGGAGTTCACAGGCCCCCACAGAAGCCCCCCGAGGCTGGCGCAC AGTCCATCCAGCCCACAGCTAACCTGGACCGGACCGATGACCTGGTGTACCTCAATGTCA TGGAGCTGGTGCGGGCCGTGCTGGAGCTCAAGAATGAGCTCTGTCAGCTGCCCCCCGAGG GCTACGTGGTGGTGGTGAAGAATGTGGGGCTGACCCTGCGGAAGCTCATCGGGAGCGTGG ATGATCTCCTGCCTTCCTTGCCGTCATCTTCACGGACAGAGATCGAGGGCACCCAGAAAC TGCTCAACAAAGACCTGGCAGAGCTCATCAACAAGATGCGGCTGGCGCAGCAGAACGCCG TGACCTCCCTGAGTGAGGAGTGCAAGAGGCAGATGCTGACGGCTTCACACACCCTGGCTG TGGACGCCAAGAACCTGCTCGACGCTGTGGACCAGGCCAAGGTTCTGGCCAATCTGGCCC ACCCACCTGCAGAGTGACGGAGGGTGGGGGCCACCTGCCTGCGTCTTCCGCCCCTGCCTG CCATGTACCTCCCCTGCCTTGCTGTTGGTCATGTGGGTCTTCCAGGGAGAAGGCCAAGGG GAGTCACCTTCCCTTGCCACTTTGCACGACGCCCTCTCCCCACCCCTACCCCTGGCTGTA CTGCTCAGGCTGCAGCTGGACAGAGGGGACTCTGGGCTATGGACACAGGGTGACGGTGAC AAAGATGGCTCAGAGGGGGACTGCTGCTGCCTGGCCACTGCTCCCTAAGCCAGCCT (SEQ ID NO: 62)

[0380] As used herein, the term "SCIMP" refers to a gene encoding an SLP adaptor and CSK interacting membrane protein. The terms "SCIMP" and "SLP adaptor and CSK interacting membrane protein" include wild-type forms of the SCIMP gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type SCIMP. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type SCIMP nucleic acid sequence (e.g., SEQ ID NO: 63, NCBI Reference Sequence: NM_207103.3). SEQ ID NO: 63 is the wild-type gene sequence encoding the SCIMP protein and is shown below. (SEQ ID NO:63)

[0381] As used herein, the term "SLC24A4" refers to the gene encoding solute carrier family 24 member 4. The terms "SLC24A4" and "solute carrier family 24 member 4" include wild-type forms of the SLC24A4 gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type SLC24A4. An example of such a variant is a nucleic acid having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type SLC24A4 nucleic acid sequence (e.g., SEQ ID NO: 64, NCBI Reference Sequence: NM_153646.3). SEQ ID NO: 64 is the wild-type gene sequence encoding the SLC24A4 protein and is shown below. (SEQ ID NO:64)

[0382] As used herein, the term "SORL1" refers to a gene encoding a sortilin-related receptor. The terms "SORL1" and "sortilin-related receptor" include wild-type forms of the SORL1 gene, as well as variants of wild-type SORL1 (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type SORL1 nucleic acid sequence (e.g., SEQ ID NO: 65, ENA Accession No. Y08110). SEQ ID NO:65 is the wild-type gene sequence encoding the SORL1 protein and is shown below. CCGGCCCAGCGGCTCTCCTGGCCTCGCGCTGCACATTCTCTCCTGGCGGCGGCGCCACCT GCAGTAGCGTTCGCCCGAACATGGCGACACGGAGCAGCAGGAGGGAGTCGCGACTCCCGT TCCTATTCACCCTGGTCGCACTGCTGCCGCCCGGAGCTCTCTGCGAAGTCTGGACGCAGA GGCTGCACGGCGGCAGCGCGCCCTTGCCCCAGGACCGGGGCTTCCTCGTGGTGCAGGGCG ACCCGCGCGAGCTGCGGCTGTGGGCGCGCGGGGATGCCAGGGGGGCGAGCCGCGCGGACG AGAAGCCGCTCCGGAGGAAACGGAGCGCTGCCCTGCAGCCCGAGCCCATCAAGGTGTACG GACAGGTTAGTCTGAATGATTCCCACAATCAGATGGTGGTGCACTGGGCTGGAGAGAAAA GCAACGTGATCGTGGCCTTGGCCCGAGATAGCCTGGCATTGGCGAGGCCCAAGAGCAGTG ATGTGTACGTGTCTTACGACTATGGAAAATCATTCAAGAAAATTTCAGACAAGTTAAACT TTGGCTTGGGAAATAGGAGTGAAGCTGTTATCGCCCAGTTCTACCACAGCCCTGCGGACA ACAAGCGGTACATCTTTGCAGACGCTTATGCCCAGTACCTCTGGATCACGTTTGACTTCT GCAACACTCTTCAAGGCTTTTCCATCCCATTTCGGGCAGCTGATCTCCTCCTACACAGTA AGGCCTCCAACCTTCTCTTGGGCTTTGACAGGTCCCACCCCAACAAGCAGCTGTGGAAGT CAGATGACTTTGGCCAGACCTGGATCATGATTCAGGAACATGTCAAGTCCTTTTCTTGGG GAATTGATCCCTATGACAAACCAAATACCATCTACATTGAACGACACGAACCCTCTGGCT ACTCCACTGTCTTCCGAAGTACAGATTTCTTCCAGTCCCGGGAAAACCAGGAAGTGATCC TTGAGGAAGTGAGAGATTTTCAGCTTCGGGACAAGTACATGTTTGCTACAAAGGTGGTGC ATCTCTTGGGCAGTGAACAGCAGTCTTCTGTCCAGCTCTGGGTCTCCTTTGGCCGGAAGC CCATGAGAGCAGCCCAGTTTGTCACAAGACATCCTATTAATGAATATTACATCGCAGATG CCTCCGAGGACCAGGTGTTTGTGTGTGTCAGCCACAGTAACAACCGCACCAATTTATACA TCTCAGAGGCAGAGGGGCTGAAGTTCTCCCTGTCCTTGGAGAACGTGCTCTATTACAGCC CAGGAGGGGCCGGCAGTGACACCTTGGTGAGGTATTTTGCAAATGAACCATTTGCTGACT TCCACCGAGTGGAAGGATTGCAAGGAGTCTACATTGCTACTCTGATTAATGGTTCTATGA ATGAGGAGAACATGAGATCGGTCATCACCTTTGACAAAGGGGGAACCTGGGAGTTTCTTC AGGCTCCAGCCTTCACGGGATATGGAGAGAAAATCAATTGTGAGCTTTCCCAGGGCTGTT CCCTTCATCTGGCTCAGCGCCTCAGTCAGCTCCTCAACCTCCAGCTCCGGAGAATGCCCA TCCTGTCCAAGGAGTCGGCTCCAGGCCTCATCATCGCCACTGGCTCAGTGGGAAAGAACT TGGCTAGCAAGACAAACGTGTACATCTCTAGCAGTGCTGGAGCCAGGTGGCGAGAGGCAC TTCCTGGACCTCACTACTACACATGGGGAGACCACGGCGGAATCATCACGGCCATTGCCC AGGGCATGGAAACCAACGAGCTAAAATACAGTACCAATGAAGGGGAGACCTGGAAAACAT TCATCTTCTCTGAGAAGCCAGTGTTTGTGTATGGCCTCCTCACAGAACCTGGGGAGAAGA GCACTGTCTTCACCATCTTTGGCTCGAACAAAGAGAATGTCCACAGCTGGCTGATCCTCC AGGTCAATGCCACGGATGCCTTGGGAGTTCCCTGCACAGAGAATGACTACAAGCTGTGGT CACCATCTGATGAGCGGGGGAATGAGTGTTTGCTGGGACACAAGACTGTTTTCAAACGGC GGACCCCCCATGCCACATGCTTCAATGGAGAGGACTTTGACAGGCCGGTGGTCGTGTCCA ACTGCTCCTGCACCCGGGAGGACTATGAGTGTGACTTCGGTTTCCAAGATGAGTGAAGATT TGTCATTAGAGGTTTGTGTTCCAGATCCGGAATTTTCTGGAAAGTCATACTCCCCTCCTG TGCCTTGCCCTGTGGGTTCTACTTACAGGAGAACGAGAGGCTACCGGAAGATTTCTGGGGG ACACTTGTAGCGGAGGAGATGTTGAAGCGCGACTGGAAGGAGAGCTGGTCCCCTGTCCCC TGGCAGAAGGAACGAGTTCATTCTGTATGCTGTGAGGAAATCCATCTACCGCTATGACC TGGCCTCGGGAGCCACCGAGCAGTTGCCTCTCACCGGGCTACGGGCAGCAGTGGCCCTGG ACTTTGACTATGAGCACAACTGTTTGTATTGGTCCGACCTGGCCTTGGACGTCATCCAGC GCCTCTGTTTGAATGGAAGCACAGGGCAAGAGGTGATCATCAATTCTGGCCTGGAGACAG TAGAAGCTTTGGCTTTTGAACCCCTCAGCCAGCTGCTTTACTGGGTAGATGCAGGCTTCA AAAAGATTGAGGTAGCTAATCCAGATGGCGACTTCCGACTCACAATCGTCAATTCCTCTG TGCTTGATCGTCCCAGGGCTCTGTCCTCGTCCAAGAGGGGGTGATGTTCTGGACAG ACTGGGGAGACCTGAAGCCTGGGATTTATCGGAGCAATATGGATGGTTCTGCTGCCTATC ACCTGGTGTCTGAGGATGTGAAGTGGCCCAATGGCATCTCTGTGGACGACCAGTGGATTT ACTGGACGGATGCCTACCTGGAGTGCATAGAGCGGATCACGTTCAGTGGCCAGCAGCGCT CTGTCATTCTGGACAACCTCCCGCACCCCTATGCCATTGCTGTCTTTAAGAATGAAATCT ACTGGGATGACTGGTCACAGCTCAGCATATTCCGAGCTTCCAAATACAGTGGGTCCCAGA TGGAGATTCTGGCAAACCAGCTCACGGGGCTCATGGACATGAAGATTTTCTACAAGGGGA AGAACACTGGAAGCAATGCCTGTGTGCCCAGGCCATGCAGCCTGCTGTGCCTGCCCAAGG CCAACAACAGTAGAAGCTGCAGGTGTCCAGAGGATGTGTCCAGCAGTGTGCTTCCATCAG GGGACCTGATGTGTGACTGCCCTCAGGGCTATCAGCTCAAGAACAATACCTGTGTCAAAG AAGAGAACACCTGTCTTCGCAACCAGTATCGCTGCAGCAACGGGAACTGTATCAACAGCA TTTGGTGGTGTGACTTTGACAACGACTGTGGAGACATGAGCGATGAGAGAAACTGCCCTA CCACCATCTGTGACCTGGACACCCAGTTTCGTTGCCAGGAGTCTGGGACTTGTATCCCAC TGTCCTATAAATGTGACCTTGAGGATGACTGTGGAGACAACAGTGATGAAAGTCATTGTG AAATGCACCAGTGCCGGAGTGACGAGTACAACTGCAGTTCCGGCATGTGCATCCGCTCCT CCTGGGTATGTGACGGGGACAACGACTGCAGGGACTGGTCTGATGAAGCCAACTGTACCG CCATCTATCACACCTGTGAGGCCTCCAACTTCCAGTGCCGAAACGGGCACTGCATCCCCC AGCGGTGGGCGTGTGACGGGGATACGGACTGCCAGGATGGTTCCGATGAGGATCCAGTCA ACTGTGAGAAGAAGTGCAATGGATTCCGCTGCCCAAACGGCACTTGCATCCCATCCAGCA AACATTGTGATGGTCTGCGTGATTGCTCTGATGGCTCCGATGAACAGCACTGCGAGCCCC TCTGTACGCACTTCATGGACTTTGTGTGTAAGAACCGCCAGCAGTGCCTGTTCCACTCCA TGGTCTGTGACGGAATCATCCAGTGCCGCGACGGGTCCGATGAGGATGCGGCGTTTGCAG GATGCTCCCAAGATCCTGAGTTCCACAAGGTATGTGATGAGTTCGGTTTCCAGTGTCAGA ATGGAGTGTGCATCAGTTTGATTTGGAAGTGCGACGGGATGGATGATTGCGGCGATTATT CTGATGAAGCCAACTGCGAAAACCCCACAGAAGCCCCAAACTGCTCCCGCTACTTCCAGT TTCGGTGTGAGAATGGCCACTGCATCCCCAACAGATGGAAATGTGACAGGGAGAACGACT GTGGGGACTGGTCTGATGAGAAGGATTGTGGAGATTCACATATTCTTCCCTTCTCGACTC CTGGGCCCTCCACGTGTCTGCCCAATTACTACCGCTGCAGCAGTGGGACCTGCGTGATGG ACACCTGGGTGTGCGACGGGTACCGAGATTGTGCAGATGGCTCTGACGAGGAAGCCTGCC CCTTGCTTGCAAACGTCACTGCTGCCTCCACTCCCACCCAACTTGGGCGATGTGACCGAT TTGAGTTCGAATGCCACCAACCGAAGACGTGTATTCCCAACTGGAAGCGCTGTGACGGCC ACCAAGATTGCCAGGATGGCCGGGACGAGGCCAATTGCCCCACACACAGCACCTTGACTT GCATGAGCAGGGAGTTCCAGTGCGAGGACGGGGAGGCCTGCATTGTGCTCTCGGAGCGCT GCGACGGCTTCCTGGACTGCTCGGACGAGAGCGATGAAAAGGCCTGCAGTGATGAGTTGA CTGTGTACAAAGTACAGAATCTTCAGTGGACAGCTGACTTCTCTGGGGATGTGACTTTGA CCTGGATGAGGCCCAAAAAAATGCCCTCTGCATCTTGTGTATATAATGTCTACTACAGGG TGGTTGGAGAGAGCATATGGAAGACTCTGGAGACCCACAGCAATAAGACAAACACTGTAT TAAAAGTCTTGAAACCAGATACCACGTATCAGGTTAAAGTACAGGTTCAGTGTCTCAGCA AGGCACACAACACCAATGACTTTGTGACCCTGAGGACCCCAGAGGGATTGCCAGATGCCC CTCGAAATCTCCAGCTGTCACTCCCCAGGGAAGCAGAAGGTGTGATTGTAGGCCACTGGG CTCCTCCCATCCACACCCATGGCCTCATCCGTGAGTACATTGTAGAATACAGCAGGAGTG GTTCCAAGATGTGGGCCTCCCAGAGGGCTGCTAGTAACTTTACAGAAATCAAGAACTTAT TGGTCAACACTCTATACACCGTCAGAGTGGCTGCGGTGACTAGTCGTGGAATAGGAAACT GGAGCGATTCTAAATCCATTACCACCATAAAAGGAAAAGTGATCCCACCACCAGATATCC ACATTGACAGCTATGGTGAAAATTATCTAAGCTTCACCCTGACCATGGAGAGTGATATCA AGGTGAATGGCTATGTGGTGAACCTTTTCTGGGCATTTGACACCCACAAGCAAGAGAGGA GAACTTTGAACTTCCGAGGAAGCATATTGTCACACAAAGTTGGCAATCTGACAGCTCATA CATCCTATGAGATTTCTGCCTGGGCCAAGACTGACTTGGGGGATAGCCCTCTGGCATTTG AGCATGTTATGACCAGAGGGGTTCGCCCACCTGCACCTAGCCTCAAGGCCAAAGCCATCA ACCAGACTGCAGTGGAATGTACCTGGACCGGCCCCCGGAATGTGGTTTATGGTATTTTCT ATGCCACGTCCTTTCTTGACCTCTATCGCAACCCGAAGAGCTTGACTACTTCACTCCACA ACAAGACGGTCATTGTCAGTAAGGATGAGCAGTATTTGTTTCTGGTCCGTGTAGTGGTAC CCTACCAGGGGCCATCCTCTGACTACGTTGTAGTGAAGATGATCCCGGACAGCAGGCTTC CACCCCGTCACCTGCATGTGGTTCATACGGGCAAAACCTCCGTGGTCATCAAGTGGGAAT CACCGTATGACTCTCCTGACCAGGACTTGTTGTATGCAATTGCAGTCAAAGATCTCATAA GAAAGACTGACAGGAGCTACAAAGTAAAATCCCGTAACAGCACTGTGGAATACACCCTTA ACAAGTTGGAGCCTGGCGGGAAATACCACATCATTGTCCAACTGGGGAACATGAGCAAAG ATTCCAGCATAAAAATTACCACAGTTTCATTATCAGCACCTGATGCCTTAAAAATCATAA CAGAAAATGATCATGTTCTTCTGTTTTGGAAAAGCCTGGCTTTAAAGGAAAAGCATTTTA ATGAAAGCAGGGGCTATGAGATACACATGTTTGATAGTGCCATGAATATCACAGCTTACC TTGGGAATACTACTGACAATTTCTTTAAAATTTCCAACCTGAAGATGGGTCATAATTACA CGTTCACCGTCCAAGCAAGATGCCTTTTTGGCAACCAGATCTGTGGGGAGCCTGCCATCC TGCTGTACGATGAGCTGGGGTCTGGTGCAGATGCATCTGCAACGCAGGCTGCCAGATCTA CGGATGTTGCTGCTGTGGTGGTGCCCATCTTATTCCTGATACTGCTGAGCCTGGGGGTGG GGTTTGCCATCCTGTACACGAAGCACCGGAGGCTGCAGAGCAGCTTCACCGCCTTCGCCA ACAGCCACTACAGCTCCAGGCTGGGGTCCGCAATCTTCTCCTCTGGGGATGACCTGGGGG AAGATGATGAAGATGCCCCTATGATAACTGGATTTTCAGATGACGTCCCCATGGTGATAG CCTGAAAGAGCTTTCCTCACTAGAAACCAAATGGTGTAAATATTTTATTTGATAAAGATA GTTGATGGTTTATTTTAAAAGATGCACTTTGAGTTGCAATATGTTATTTTTATATGGGCC (SEQ ID NO:65)

[0383] As used herein, the term "SPI1" refers to a gene encoding the transcription factor PU.1. The terms "SPI1" and "transcription factor PU.1" include wild-type forms of the SPI1 gene, as well as variants of wild-type SPI1 (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type SPI1 nucleic acid sequence (e.g., SEQ ID NO: 66, ENA Accession No. X52056). SEQ ID NO:66 is the wild-type gene sequence encoding the SPI1 protein and is shown below. AAAATCAGGAACTTGTGCTGGCCCTGCAATGTCAAGGGAGGGGGCTCACCCAGGGCTCCT GTAGCTCAGGGGGCAGGCCTGAGCCCTGCACCCGCCCCACGACCGTCCAGCCCCTGACGG GCACCCCATCCTGAGGGGCTCTGCATTGGCCCCCACCGAGGCAGGGGATCTGACCGACTC GGAGCCCGGCTGGATGTTACAGGCGTGCAAAATGGAAGGGTTTCCCCTCGTCCCCCCTCC ATCAGAAGACCTGGTGCCCTATGACACGGATCTATACCAACGCCAAACGCACGAGTATTA CCCCTATCTCAGCAGTGATGGGGAGAGCCATAGCGACCATTACTGGGACTTCCACCCCCA CCACGTGCACAGCGAGTTCGAGAGCTTCGCCGAGAACAACTTCACGGAGCTCCAGAGCGT GCAGCCCCCGCAGCTGCAGCAGCTCTACCGCCACATGGAGCTGGAGCAGATGCACGTCCT CGATACCCCCATGGTGCCACCCCATCCCAGTCTTGGCCACCAGGTCTCCTACCTGCCCCG GATGTGCCTCCAGTACCCATCCCTGTCCCCAGCCCAGCCCAGCTCAGATGAGGAGGAGGG CGAGCGGCAGAGCCCCCCACTGGAGGTGTCTGACGGCGAGGCGGATGGCCTGGAGCCCGG GCCTGGGCTCCTGCCTGGGGAGACAGGCAGCAAGAAGAAGATCCGCCTGTACCAGTTCCT GTTGGACCTGCTCCGCAGCGGCGACATGAAGGACAGCATCTGGTGGGTGGACAAGGACAA GGGCACCTTCCAGTTCTCGTCCAAGCACAAGGAGGCGCTGGCGCACCGCTGGGGCATCCA GAAGGGCAACCGCAAGAAGATGACCTACCAGAAGATGGCGCGCGCGCTGCGCAACTACGG CAAGACGGGCGAGGTCAAGAAGGTGAAGAAGAAGCTCACCTACCAGTTCAGCGGCGAAGT GCTGGGCCGCGGGGGCCTGGCCGAGCGGCGCCACCCGCCCCACTGAGCCCGCAGCCCCCG CCGGCCCCGCCAGGCCTCCCCGCTGGCCATAGCATTAAGCCCTCGCCCGGCCCGGACACA GGGAGGACGCTCCCGGGGCCCAGAGGCAGGACTGTGGCGGGCCGGGCTCCGTCACCCGCC CCTCCCCCCACTCCAGGCCCCCTCCACATCCCGCTTCGCCTCCCTCCAGGACTCCACCCC GGCTCCCGACGCCAGCTGGGCGTCAGACCCACCGGCAACCTTGCAGAGGACGACCCGGGG TACTGCCTTGGGAGTCTCAAGTCCGTATGTAAATCAGATCTCCCCTCTCACCCCTCCCAC CCATTAACCTCCTCCCAAAAAACAAGTAAAGTTATTCTCAATCC (SEQ ID NO:66)

[0384] As used herein, the term "SPP1" refers to the gene encoding secreted phosphoprotein 1. The terms "SPP1" and "secreted phosphoprotein 1" include wild-type forms of the SPP1 gene, as well as variants of the wild-type SPP1 (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type SPP1 nucleic acid sequence (e.g., SEQ ID NO: 67, NCBI Reference Sequence: NM_001040058.1). SEQ ID NO: 67 is the wild-type gene sequence encoding the SPP1 protein and is shown below. (SEQ ID NO:67)

[0385] As used herein, the term "SPPL2A" refers to the gene encoding signal peptide peptidase-like 2A. The terms "SPPL2A" and "signal peptide peptidase-like 2A" include wild-type forms of the SPPL2A gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type SPPL2A. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type SPPL2A nucleic acid sequence (e.g., SEQ ID NO: 68, NCBI Reference Sequence: NM_001040058.1). SEQ ID NO: 68 is the wild-type gene sequence encoding the SPPL2A protein and is shown below. (SEQ ID NO:68)

[0386] As used herein, the term "TBK1" refers to the gene encoding the serine / threonine-protein kinase TBK1. The terms "TBK1" and "serine / threonine-protein kinase TBK1" include wild-type forms of the TBK1 gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type TBK1. An example of such a variant is a nucleic acid having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type TBK1 nucleic acid sequence (e.g., SEQ ID NO: 69, ENA Accession No. AF191838). SEQ ID NO: 69 is the wild-type gene sequence encoding the TBK1 protein and is shown below. GCCGGCGGTGGCGCGGCGGAGACCCGGCTGGTATAACAAGAGGATTGCCTGATCCAGCCA AGATGCAGAGCACTTCTAATCATCTGTGGCTTTTATCTGATATTTTAGGCCAAGGAGCTA CTGCAAATGTCTTTCGTGGAAGACATAAGAAAACTGGTGATTTATTTGCTATCAAAGTAT TTAATAACATAAGCTTCCTTCGTCCAGTGGATGTTCAAATGAGAGAATTTGAAGTGTTGA AAAAACTCAATCACAAAAATATTGTCAAATTATTTGCTATTGAAGAGGAGACAACAACAA GACATAAAGTACTTATTATGGAATTTTGTCCATGTGGGAGTTTATACACTGTTTTAGAAG AACCTTCTAATGCCTATGGACTACCAGAATCTGAATTCTTAATTGTTTTGCGAGATGTGG TGGGTGGAATGAATCATCTACGAGAGAATGGTATAGTGCACCGTGATATCAAGCCAGGAA ATATCATGCGTGTTATAGGGGAAGATGGACAGTCTGTGTACAAACTCACAGATTTTGGTG CAGCTAGAGAATTAGAAGATGATGAGCAGTTTGTTTCTCTGTATGGCACAGAAGAATATT TGCACCCTGATATGTATGAGAGAGCAGTGCTAAGAAAAGATCATCAGAAGAAATATGGAG CAACAGTTGATCTTTGGAGCATTGGGGTAACATTTTACCATGCAGCTACTGGATCACTGC CATTTAGACCCTTTGAAGGGCCTCGTAGGAATAAAGAAGTGATGTATAAAATAATTACAG GAAAGCCTTCTGGTGCAATATCTGGAGTACAGAAAGCAGAAAATGGACCAATTGACTGGA GTGGAGACATGCCTGTTTCTTGCAGTCTTTCTCGGGGTCTTCAGGTTCTACTTACCCCTG TTCTTGCAAACATCCTTGAAGCAGATCAGGAAAAGTGTTGGGGTTTTGACCAGTTTTTTG CAGAAACTAGTGATATACTTCACCGAATGGTAATTCATGTTTTTTCGCTACAACAAATGA CAGCTCATAAGATTTATATTCATAGCTATAATACTGCTACTATATTTCATGAACTGGTAT ATAAACAAACCAAAATTATTTCTTCAAATCAAGAACTTATCTACGAAGGGCGACGCTTAG TCTTAGAACCTGGAAGGCTGGCACAACATTTCCCTAAAACTACTGAGGAAAACCCTATAT TTGTAGTAAGCCGGGAACCTCTGAATACCATAGGATTAATATGAAAAAATTTCCCTCC CTAAAGTACATCCACGTTATGATTTAGACGGGGATGCTAGCATGGCTAAGGCAATAACAG GGGTTGTGTGTTATGCCTGCAGAATTGCCAGTACCTTACTGCTTTATCAGGAATTAATGC GAAAGGGGATACGATGGCTGATTGAATTAATTAAAGATGATTACAATGAAACTGTTCACA AAAAGACAGAAGTTGTGATCACATTGGATTTCTGTATCAGAAACATTGAAAAAACTGTGA AAGTATATGAAAAGTTGATGAAGATCAACCTGGAAGCGGCAGAGTTAGGTGAAATTTCAG ACATACACACCAAATTGTTGAGACTTTCCAGTTCTCAGGGAACAATAGAAACCAGTCTTC AGGATATCGACAGCAGATTATCTCCAGGTGGATCACTGGCAGACGCATGGGCACATCAAG AAGGCACTCATCCGAAAGACAGAAATGTAGAAAAACTACAAGTCCTGTTAAATTGCATGA CAGAGATTTACTATCAGTTCAAAAAAGACAAAGCAGAACGTAGATTAGCTTATAATGAAG AACAAATCCACAAATTTGATAAGCAAAAACTGTATTACCATGCCACAAAAGCTATGACGC ACTTTACAGATGAATGTGTTAAAAAGTATGAGGCATTTTTGAATAAGTCAGAAGAATGGA TAAGAAAGATGCTTCATCTTAGGAAACAGTTATTATCGCTGACTAATCAGTGTTTTGATA TTGAAGAAGAGTATCAAAATATCAAGAATATACTAATGAGTTACAAGAAACTCTGCCTC AGAAAATGTTTACAAGCTTCCAGTGGAATCAAACATACCATGACCCCAATTTATCCAAGTT CTAACACATTAGTAGAAATGACTCTTGGTATGAAGAAATTAAAGGAAGAGATGGAAGGGG TGGTTAAAGAACTTGCTGAAAATAACCACATTTTAGAAAGGTTTGGCTCTTTAACCATGG ATGGTGGCTTCGCAACGTTGACTGTCTTTAGCTTTCTAATAGAAGTTTAAGAAAAGTTT CCGTTTGCACAAGAAAATAACGCTTGGGCATTAAATGAATGCCTTTATAGATAGTCACTT GTTTCTACAATTCAGTATTTGATGTGGTCGTGTAAATATGTACAATATTGTAAATACATA AAAAATATACAAATTTTTGGCTGCTGTGAAGATGTAATTTTATCTTTTAACATTTATAAT TATATGAGGAAATTTGACCTCAGTGATCACGAGAAGAAAGCCATGACCGACCAATATGTT GACATACTGATCCTCTACTCTGAGTGGGGCTAAATAAGTTATTTTCTCTGACCGCCTACT GGAAATATTTTTAAGTGGAACCAAAATAGGCATCCTTACAAATCAGGAAGACTGACTTGA CACGTTTGTAAATGGTAGAACGGTGGCTACTGTGAGTGGGGAGCAGAACCGCACCACTGT TATACTGGGATAACAATTTTTTTGAGAAGGATAAAGTGGCATTATTTTATTTTACAAGGT GCCCAGATCCCAGTTATCCTTGTATCCATGTAATTTCAGATGAATTATTAAGCAAACATT TTAAAGT (SEQ ID NO:69)

[0387] As used herein, the term "TNF" refers to a gene encoding tumor necrosis factor. The terms "TNF" and "tumor necrosis factor" include wild-type forms of the TNF gene, as well as mutant forms (e.g., splice variants and polymorphisms) of wild-type TNF. Examples of such mutants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type TNF nucleic acid sequence (e.g., SEQ ID NO: 70, ENA Accession No. X01394). SEQ ID NO:70 is the wild-type gene sequence encoding the TNF protein and is shown below. GCAGAGGACCAGCTAAGAGGGAGAGAAGCAACTACAGACCCCCCTGAAAACAACCCTCA GACGCCACATCCCCTGACAAGCTGCCAGGCAGGTTCTCTTCCTCTCACATACTGACCCAC GGCTCCACCCTCTCTCCCCTGGAAAGGACACCATGAGCACTGAAAGCATGATCCGGGACG TGGAGCTGGCCGAGGAGGCGCTCCCCAAGAAGACAGGGGGGCCCCAGGGCTCCAGGCGGT GCTTGTTCCTCAGCCTCTTCTCCTTCCTGATCGTGGCAGGCGCCACCACGCTCTTCTGCC TGCTGCACTTTGGAGTGATCGGCCCCCAGAGGGAAGAGTTCCCCAGGGACCTCTCTCTAA TCAGCCCTCTGGCCCAGGCAGTCAGATCATCTTCTCGAACCCCGAGTGACAAGCCTGTAG CCCATGTTGTAGCAAACCCTCAAGCTGAGGGGCAGCTCCAGTGGCTGAACCGCCGGGCCA ATGCCCTCCTGGCCAATGGCGTGGAGCTGAGAGATAACCAGCTGGTGGTGCCATCAGAGG GCCTGTACCTCATCTACTCCCAGGTCCTCTTCAAGGGCCAAGGCTGCCCCTCCACCCATG TGCTCCTCACCCACACCATCAGCCGCATCGCCGTCTCCTACCAGACCAAGGTCAACCTCC TCTCTGCCATCAAGAGCCCCTGCCAGAGGGAGACCCCAGAGGGGGCTGAGGCCAAGCCCT GGTATGAGCCCATCTATCTGGGAGGGGTCTTCCAGCTGGAGAAGGGTGACCGACTCAGCG CTGAGATCAATCGGCCCGACTATCTCGACTTTGCCGAGTCTGGGCAGGTCTACTTTGGGA TCATTGCCCTGTGAGGAGGACGAACATCCAACCTTCCCAAACGCCTCCCCTGCCCCAATC CCTTTATTACCCCCTCCTTCAGACACCCTCAACCTCTTCTGGCTCAAAAAGAGAATTGGG GGCTTAGGGTCGGAACCCAAGCTTAGAACTTTAAGCAACAAGACCACCACTTCGAAACCT GGGATTCAGGAATGTGTGGCCTGCACAGTGAATTGCTGGCAACCACTAAGAATTCAAACT GGGGCCTCCAGAACTCACTGGGGCCTACAGCTTTGATCCCTGACATCTGGAATCTGGAGA CCAGGGAGCCTTTGGTTCTGGCCAGAATGCTGCAGGACTTGAGAAGACCTCACCTAGAAA TTGACACAAGTGGACCTTAGGCCTTCCTCTCTCCAGATGTTTCCAGACTTCCTTGAGACA CGGAGCCCAGCCCTCCCCATGGAGCCAGCTCCCTCTATTTATGTTTGCACTTGTGATTAT TTATTATTTATTTATTATTTATTTATTTACAGATGAATGTATTTATTTGGGAGACCGGGG TATCCTGGGGGACCCAATGTAGGAGCTGCCTTGGCTCAGACATGTTTTCCGTGAAAACGG AGCTGAACAATAGGCTGTTCCCATGTAGCCCCCTGGCCTCTGTGCCTTCTTTTGATTATG TTTTTTAAAATATTTATCTGATTAAGTTGTCTAAACAATGCTGATTTGGTGACCAACTGT CACTCATTGCTGAGCCTCTGCTCCCCAGGGGAGTTGTGTCTGTAATCGCCCTACTATTCA GTGGCGAGAAATAAAGTTTGCTT (SEQ ID NO: 70)

[0388] As used herein, the term "TREM2" refers to a gene encoding a triggering receptor expressed on myeloid cells 2. The terms "TREM2" and "triggering receptor expressed on myeloid cells 2" include the wild-type form of the TREM2 gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type TREM2. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type TREM2 nucleic acid sequence (e.g., SEQ ID NO: 71, ENA Accession No. AF213457). SEQ ID NO: 71 is the wild-type gene sequence encoding the TREM2 protein and is shown below. TGACATGCCTGATCCTTCTTTTCTGCAGTTCAAGGGAAAGACGAGATCTTTGCACAAGGC ACTCTGCTTCTGCCCTTGGCTGGGGAAGGGTGGCATGGAGCCTCTCCGGCTGCTCATCTT ACTCTTTGTCACAGAGCTGTCCGGAGCCCACAACACCACAGTGTTCCAGGGCGTGGCGGG CCAGTCCCTGCAGGTGTCTTGCCCCTATGACTCCATGAAGCACTGGGGGAGGCGCAAGGC CTGGTGCCGCCAGCTGGGGAGAGAAGGGCCCATGCCAGCGTGTGGTCAGCACGCACAACTT GTGGCTGCTGTCCTTCCTGAGGAGGTGGAATGGGAGCACAGCCATCACAGACGATACCCT GGGTGGCACTCTCACCATTACGCTGCGGAATCTACAACCCCATGATGCGGGTCTCTACCA GTGCCAGAGCCTCCATGGCAGTGAGGCTGACACCCTCAGGAAGGTCCTGGTGGAGGTGCT GGCAGACCCCCTGGATCACCGGGATGCTGGAGATCTCTGGTTCCCCGGGGAGTCTGAGAG CTTCGAGGATGCCCATGTGGAGCACAGCATCTCCAGGAGCCTCTTGGAAGGAGAAATCCC CTTCCCACCCACTTCCATCCTTCTCCTCCTGGCCTGCATCTTTCTCATCAAGATTCTAGC AGCCAGCGCCCTCTGGGCTGCAGCCTGGCATGGACAGAAGCCAGGGACACATCCACCCAG TGAACTGGACTGTGGCCATGACCCAGGGTATCAGCTCCAAACTCTGCCAGGGCTGAGAGA CACGTGAAGGAAGATGATGGGAGGAAAAGCCCAGGAGAAGTCCCACCAGGGACCAGCCCA GCCTGCATACTTGCCACTTGGCCACCAGGACTCCTTGTTCTGCTCTGGCAAGAGACTACT CTGCCTGAACACTGCTTCTCCTGGACCCTGGAAGCAGGGACTGGTTGAGGGAGTGGGGAG GTGGTAAGAACACCTGACAACTTCTGAATATTGGACATTTTAAACACTTACAAATAAATC CAAGACTGTCATATTTAAAAA (SEQ ID NO: 71)

[0389] As used herein, the term "TREML2" refers to the gene encoding a triggering receptor expressed on myeloid-like cells 2. The terms "TREML2" and "triggering receptor expressed on myeloid-like cells 2" include wild-type forms of the TREML2 gene, as well as mutant forms (e.g., splice variants and polymorphisms) of the wild-type TREML2. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type TREML2 nucleic acid sequence (e.g., SEQ ID NO: 72, NCBI Reference Sequence: NM_024807.3). SEQ ID NO: 72 is the wild-type gene sequence encoding the TREML2 protein and is shown below. (SEQ ID NO:72)

[0390] As used herein, the term "TYROBP" refers to the gene encoding the TYRO protein tyrosine kinase binding protein. The terms "TYROBP" and "TYRO protein tyrosine kinase binding protein" include wild-type forms of the TYROBP gene, as well as variants of the wild-type TYROBP (e.g., splice variants and polymorphisms). Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to the wild-type TYROBP nucleic acid sequence (e.g., SEQ ID NO: 73, ENA Accession No. AF019562). SEQ ID NO: 73 is the wild-type gene sequence encoding the TYROBP protein and is shown below. CCACGCGTCCGCGCTGCGCCACATCCCACCGGCCCTTACACTGTGGTGTCCAGCAGCATC CGGCTTCATGGGGGGACTTGAACCCTGCAGCAGGCTCCTGCTCCTGCCTCTCCTGCTGGC TGTAAGTGGTCTCCGTCCTGTCCAGGCCCAGGCCCAGAGCGATTGCAGTTGCTCTACGGT GAGCCCGGGCGTGCTGGCAGGGATCGTGATGGGAGACCTGGTGCTGACAGTGCTCATTGC CCTGGCCGTGTACTTCCTGGGCCGGCTGGTCCCTCGGGGGCGAGGGGCTGCGGAGGCAGC GACCCGGAAACAGCGTATCACTGAGACCGAGTCGCCTTATCAGGAGCTCCAGGGTCAGAG GTCGGATGTCTACAGCGACCTCAACACACAGAGGCCGTATTACAAATGAGCCCGAATCAT GACAGTCAGCAACATGATACCTGGATCCAGCCATTCCTGAAGCCCACCCTGCACCTCATT CCAACTCCTACCGCGATACAGACCCACAGAGTGCCATCCCTGAGAGACCAGACCGCTCCC CAATACTCTCCTAAAATAAACATGAAGCACAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA (SEQ ID NO:73)

[0391] As used herein, the term "ZCWPW1" refers to the gene encoding zinc finger CW-type PWWP domain protein 1. The terms "ZCWPW1" and "zinc finger CW-type PWWP domain protein 1" include wild-type forms of the ZCWPW1 gene, as well as variants (e.g., splice variants and polymorphisms) of the wild-type ZCWPW1. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% or more identity) to a wild-type ZCWPW1 nucleic acid sequence (e.g., SEQ ID NO: 74, ENA Accession No. AL136735). SEQ ID NO: 74 is the wild-type gene sequence encoding the ZCWPW1 protein and is shown below. CGCCGTTTTCCCGGGGAGATGCGCCGCCCGGTCTCCCTGCCAGCGGAGTGCTGGGCCGAG GACAGGGCGGCAGGGGTGACAGTGGGGTCCAGGAGAGTCTCAAAATCCTAAGCTTTCAGT ATTTGTTATTGTGAAAGAAGTTAATTCACCTGAAACAGAGGAGGGGCAACCTGAGTTATC AGAAAGTGACTTCCTGGCCTTCCCTTCTTACTGATCAGAGGCACACCAAAGCGTAGTTTC TAAGCTGAATGATGACAACGTTGCAGAATAAAGAAGAATGTGGAAAGGGACCAAAGAGAA TCTTTGCCCACCTGCCAAAAATCTTACAGCCTGTTACCTTGTAGCCCTAACTCCCCTA AGGAGGAGACCCCGGGGATCAGTTCCCCAGAGACAGAGGCCCAGGATAAGCCTGCCAAAGG CCAGTTTAAAGAAGAAAGAGGAAAAAAGCAACCATGAAGAATGTTCCAAGCAGGGAACAGG AGAAAAAAAGAAGGCACAAATCAACAAGCAAGCAGAGAAGAAAAAAAGGAAAAAATCAA GTCTTCACCAATGCAGAATTTGAGGAGATTGTCCAGATTGTTCTGCAGAAGTCCCTTCAGG AGTGCTTGGGGATGGGATCTGGCCTTGATTTTGCAGAGACTTCTTGTGCCCAGCCCGTAG TATCTACCCAATCGACAAGGAGCCAGGAATTACTGCTTCTGCTACTGATACTGATAATG CTAATGGAGAGGAGGTACCACATACTCAAGAGATTTCAGTGTCTTGGGAAGGTGAAGCTG CCCCTGAGATAAGGACATCTAAGTTAGGCCAGCCAGATCCTGCACCCCTTAAGAAGAAAT CCAATAGACTCACCTTAAAGCAAAAGAAAGAAGGAAGCTCATGAGAAGGTGGAGAAAACTC AAGGTGGACATGAGCACAGACAGGAAGACCGACTAAAGAAAACAGTTCAGGATCATTCTC AGATCAGGGACCAGCAAAAGGAGAGATAAGTGGTTTTGGTCAATGTCTGGTCTGGGTCC AGTGTTCCTTCCCAAACTGTGGGAAATGGAGGCGGCTGTGTGGGAACATTGACCCCTCAG TTCTCCCAGATAATTGGTCCTGTGATCAGAACACAGATGTGCAGTATAATCGCTGTGATA TTCCTGAGGAGACCTGGACAGGGCTTGAGAGTGATGTGGCCTATGCCTCCTCACATCCAG GATCCATCATCTGGGCCAAGCAATACGGTTACCCTGGTGGCCAGGCATGATAGAATCTG ATCCTGACTTAGGGGAATATTTCTTTTTACTTCCCATCTTGATTCCCTGCCGTCTAAGT ACCATGTGACGTTTTTTGGAAACAGTTTCTCGTGCATGGATCCCAGTCAACATGCTAA AGAACTTCCAGGAGCTGTCCCTGGAGCTATCAGTCCATGAAAAGCGCAGAAATGACTGCA GCCAGAAACTGGGGGTGGCCCTGATGATGGCTCAAGAGGCAGAACAGATCAGCATTCAGG AACGGGTTAACTTGTTTGGTTTCTGGAGCCGATTCAACGGATCTAACAGTAATGGGGAAAA GAAAAGACTTACAGCTCTCTGGTTTGAACAGCCCAGGATCCTGCTTAGAGAAAAAGGA AAGAGGAAGAGTTGGAAAGGAGGAGGAGAGAAACAGACCCAATTTTGCCCATTCGTA AGCGAGTCAAAATACAGACCCAAAAAACCAAGCCAAGAGGGCTTGGGGGTGATGCAGGC ACAGCAGATGGCCGAGGCAGGACACTGCAGAGGAAGATAATGAAGAGATCTCTAGGCAGG AAATCCACAGCTCCTCCTGCACCCAGAATGGGAAGGAAAGAAGGCCAAGGGAATTCAGAT TCTGACCAGCCAGGCCCTAAGAAAAAATTTAAAGCTCCCAGAGCAAGGCCTTGGCAGCC AGCTTTTCAGAGGGAAAAGAAGTTAGAACAGTGCCAAAGAACCTGGGCCTATCAGCGTGT AAGGGGGCCTGCCCCTCATCTGCGAAAGAAGAGCCCAGACACCGGGAACCCCTGACCCAG GAGGCTGGAAGTGTCCCCCTTGAGGACGAAGCCTCCAGTGACCTGGACCTGGAGCAACTC ATGGAAGATGTTGGGAGAGAGCTGGGGCAGAGCGGGGAGCTGCAGCACAGCAACAGTGAT GGCGAGGACTTCCCCGTGGCGCTGTTTGGGAAGTAGCTGGTGCTCCTCTGCTCCCTCTTT TTCTCCCTTCTCTGGGGCGCAGGAGGGAGAAGTTGCTAAGTGCTGGGTCTGTTCATTGGC TATGAGGTTCAAATGTGTGTGGTGCAGTTTCTGTGTTAATAAAGCAGGTTACAGTCGAAA AAAAAAAAAAAAAAA (SEQ ID NO:74)

[0392] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention provides new forms of siRNA, including single-stranded and double-stranded short interfering RNA (ds-siRNA), and methods for their use in treating patients in need of microglial gene silencing (e.g., patients with dysregulated microglial gene expression, such as those with Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, frontotemporal dementia, Huntington's disease, multiple sclerosis, or progressive supranuclear palsy). The branched siRNAs of the present invention have demonstrated a surprising ability to penetrate cells. The branched compositions described herein may employ a variety of modifications known in the art and previously unknown. The siRNAs of the present invention may comprise an antisense strand comprising a region represented by formula IX, Z-((AP-) n (BP-) m ) q (IX) wherein Z is a 5' phosphorus stabilizing moiety...

Claims

[Claim 1] The invention described in the specification and drawings.

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