Method for determining genetic predisposition to cognitive function

Abstract

To provide means for simple and precise determination of the genetic predisposition to susceptibility to decline in a cognitive function.SOLUTION: A method for determining the genetic predisposition to susceptibility to a decline in cognitive function is provided, comprising: a step of detecting, in a DNA-containing sample collected from a subject, at least one group of alleles selected from the group consisting of one or two or more single nucleotide polymorphism (SNP) alleles from a short-term memory ability determination allele group, one or two or more SNP alleles from a working memory ability determination allele group, and one or two or more SNP alleles from a planning / execution ability determination allele group, or alleles of SNPs linked in disequilibrium with these SNPs; and a step of determining that the subject is susceptible to decline in a cognitive function when at least one of the bases of the detected alleles is a risk allele.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for determining genetic predisposition of cognitive function. More specifically, the present invention relates to a method for determining genetic predisposition to cognitive decline by detecting single nucleotide polymorphisms (SNPs) related to cognitive function, and a kit used for the method.

Background Art

[0002] Cognitive function is a brain function for correctly understanding information obtained from the outside and appropriately executing it. Specifically, it includes intellectual functions such as memory, thinking, language, understanding, and calculation. Furthermore, processes such as prediction, planning, judgment, self-awareness, executive function, and decision-making are also included in cognitive function, and these cognitive functions are extremely important functions that are indispensable for leading a social life. However, it is known that these cognitive functions decline with aging (Non-Patent Document 1).

[0003] Memory ability is classified according to the retention time after obtaining information and the content of the information. In the classification of psychology, there are sensory memory, short-term memory, and long-term memory, and in the classification of clinical neurology, they correspond to immediate memory, recent memory, and remote memory, respectively. Those with a retention time of several seconds are called sensory memory or immediate memory, those with a retention time of several minutes to several hours are called short-term memory or recent memory, and those with a retention time of several days to several weeks or more are called long-term memory or remote memory. In addition, memory whose content can be recalled consciously as an image or language and whose content can be stated is called declarative memory or explicit memory, and memory whose content cannot be recalled consciously and whose content cannot be stated through language or the like is called non-declarative memory or implicit memory. Declarative (explicit) memory includes episodic memory and semantic memory. Non-declarative (implicit) memory includes procedural memory, priming, classical conditioning, non-associative learning, and the like.

[0004] In daily life, cognitive functions are interrelated with each other. For example, when having a conversation, doing mental arithmetic, reading and understanding a text, a brain function called working memory is at work. Working memory is a brain function that holds the information acquired as sensory memory in mind for several seconds to dozens of seconds and uses it to execute other cognitive functions such as decision-making, calculation, speech, and thinking.

[0005] The evaluation of cognitive functions can examine each element included in cognitive functions in detail according to the method. For example, the Mnemonic similarity task (MST) is a method for evaluating memory ability, and indicators such as "short-term memory", "judgment", "attention", and "concentration" can be obtained. That is, it is possible to evaluate the function of understanding, remembering, and recalling what has been seen. The N-back task is a method for evaluating working memory, and indicators such as "sensory memory", "judgment", "attention", "concentration", and "prediction" can be obtained. That is, it is possible to evaluate the function of processing the next information while remembering what has been seen or heard. The Tower of London test or the Tower of Hanoi task is a method for evaluating the execution function, working memory, and planning (planning ability), and indicators such as "sensory memory", "judgment", "attention", "concentration", and "prediction" can be obtained. That is, it is possible to evaluate the function of planning and executing up to the goal.

[0006] One of the diseases that cause disorders in cognitive functions is Alzheimer's disease (Alzheimer's type dementia). Alzheimer's disease is thought to cause disorders in cognitive functions by causing damage and cell death of nerve cells due to the accumulation of proteins such as amyloid-β in the brain.

[0007] Heretofore, methods for evaluating the onset risk of diseases using genes and single nucleotide polymorphisms (SNPs) that have been suggested to be associated with Alzheimer's disease have been known (Non-Patent Document 2, Patent Document 1). However, little research has been conducted on the search for genes and SNPs that can predict the susceptibility to cognitive decline in healthy individuals.

Prior Art Documents

Patent Documents

[0008]

Patent Document 1

Non-Patent Documents

[0009]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0010] An object of the present invention is to provide a means for accurately and simply determining the genetic factors of the susceptibility to cognitive decline.

Means for Solving the Problems

[0011] As a result of intensive research to solve the above problems, the present inventors have found a single nucleotide polymorphism (SNP) related to the genetic predisposition to the susceptibility of cognitive function decline, and have completed the present invention.

[0012] That is, the present invention includes the following inventions. [1] A method for determining a genetic predisposition to the susceptibility of cognitive function decline, comprising: detecting at least one group of alleles selected from the group consisting of alleles of one or more single nucleotide polymorphisms (SNPs) in group A, alleles of one or more single nucleotide polymorphisms (SNPs) in group B, and alleles of one or more single nucleotide polymorphisms (SNPs) in group C, for a DNA-containing sample collected from a subject; and determining that the subject is susceptible to cognitive function decline when at least one of the bases of the detected alleles is a risk allele. Group A (allele group for determining short-term memory ability): (a1) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 1 (SNP identified by SNP: ID rs11643122, risk allele is C), or a SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 1 (SNP identified by SNP: ID rs11643122, risk allele is C) (a2) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 3 (SNP identified by SNP: ID rs2162765, risk allele is C), or a SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 3 (SNP identified by SNP: ID rs2162765, risk allele is C) (a3) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 6 (SNP identified by SNP: ID rs3806915, risk allele is C), or a SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 6 (SNP identified by SNP: ID rs3806915, risk allele is C) (a4) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 9 (SNP: the SNP identified by SNP ID rs12997044, the risk allele is C), or an SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 9 (SNP: the SNP identified by SNP ID rs12997044, the risk allele is C) Group B (working memory ability determination allele group): (b1) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 12 (SNP: the SNP identified by SNP ID rs9567703, the risk allele is G), or an SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 12 (SNP: the SNP identified by SNP ID rs9567703, the risk allele is G) (b2) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 15 (SNP: the SNP identified by SNP ID rs17360733, the risk allele is A), or an SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 15 (SNP: the SNP identified by SNP ID rs17360733, the risk allele is A) (b3) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 18 (SNP: the SNP identified by SNP ID rs1039044, the risk allele is A), or an SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 18 (SNP: the SNP identified by SNP ID rs1039044, the risk allele is A) (b4) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 21 (SNP: the SNP identified by SNP ID rs7782570, the risk allele is T), or an SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 21 (SNP: the SNP identified by SNP ID rs7782570, the risk allele is T) (b5) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 24 (SNP: the SNP identified by SNP ID rs3789002, the risk allele is G) (b6) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 25 (SNP: the SNP identified by ID rs13270610, the risk allele is A), or an SNP in linkage disequilibrium with a coefficient r2≧0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 25 (SNP: the SNP identified by ID rs13270610, the risk allele is A) (b7) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 28 (SNP: the SNP identified by ID rs7829349, the risk allele is T), or an SNP in linkage disequilibrium with a coefficient r2≧0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 28 (SNP: the SNP identified by ID rs7829349, the risk allele is T) Group C (Planning and Execution Ability Judgment Allele Group): (c1) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 31 (SNP: the SNP identified by ID rs139889875, the risk allele is T), or an SNP in linkage disequilibrium with a coefficient r2≧0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 31 (SNP: the SNP identified by ID rs139889875, the risk allele is T) (c2) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 33 (SNP: the SNP identified by ID rs9995443, the risk allele is T), or an SNP in linkage disequilibrium with a coefficient r2≧0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 33 (SNP: the SNP identified by ID rs9995443, the risk allele is T) (c3) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 36 (SNP: the SNP identified by ID rs79986676, the risk allele is T), or an SNP in linkage disequilibrium with a coefficient r2≧0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 36 (SNP: the SNP identified by ID rs79986676, the risk allele is T) (c4) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 38 (SNP: the SNP identified by SNP ID rs9375677, the risk allele is T), or an SNP in linkage disequilibrium with a coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 38 (SNP: the SNP identified by SNP ID rs9375677, the risk allele is T) (c5) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 41 (SNP: the SNP identified by SNP ID rs1106123, the risk allele is T)

[0013] [2] The SNP in linkage disequilibrium with a coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 1 in (a1) (SNP: the SNP identified by SNP ID rs11643122, the risk allele is C) is the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 2 (SNP: the SNP identified by SNP ID rs76800139, the risk allele is G), The SNP in linkage disequilibrium with a coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 3 in (a2) (SNP: the SNP identified by SNP ID rs2162765, the risk allele is C) is the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 4 (SNP: the SNP identified by SNP ID rs7705063, the risk allele is G), or the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 5 (SNP: the SNP identified by SNP ID rs2913765, the risk allele is T), The SNP in linkage disequilibrium with a coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 6 in (a3) (SNP: the SNP identified by SNP ID rs3806915, the risk allele is C) is the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 7 (SNP: the SNP identified by SNP ID rs9327010, the risk allele is G), or the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 8 (SNP: the SNP identified by SNP ID rs28489253, the risk allele is A), The method according to [1], wherein the SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 9 in (a4) (SNP: the SNP identified by SNP ID rs12997044, the risk allele is C) and having a linkage disequilibrium coefficient r2≧0.8 is the SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 10 (SNP: the SNP identified by SNP ID rs34355132, the risk allele is G), or the SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 11 (SNP: the SNP identified by SNP ID rs2287412, the risk allele is A). [3] The SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 12 in (b1) (SNP: the SNP identified by SNP ID rs9567703, the risk allele is G) and having a linkage disequilibrium coefficient r2≧0.8 is the SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 13 (SNP: the SNP identified by SNP ID rs912435, the risk allele is T), or the SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 14 (SNP: the SNP identified by SNP ID rs912430, the risk allele is G), [4] The SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 15 in (b2) (SNP: the SNP identified by SNP ID rs17360733, the risk allele is A) and having a linkage disequilibrium coefficient r2≧0.8 is the SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 16 (SNP: the SNP identified by SNP ID rs16852393, the risk allele is G), or the SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 17 (SNP: the SNP identified by SNP ID rs6703721, the risk allele is T), An SNP that has a linkage disequilibrium coefficient r2 ≥ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 18 of (b3) (SNP: the SNP identified by SNP ID rs1039044, the risk allele is A) is the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 19 (SNP: the SNP identified by SNP ID rs264702, the risk allele is T), or the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 20 (SNP: the SNP identified by SNP ID rs35780513, the risk allele is A), An SNP that has a linkage disequilibrium coefficient r2 ≥ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 21 of (b4) (SNP: the SNP identified by SNP ID rs7782570, the risk allele is T) is the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 22 (SNP: the SNP identified by SNP ID rs79424388, the risk allele is G), or the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 23 (SNP: the SNP identified by SNP ID rs1971646, the risk allele is G), An SNP that has a linkage disequilibrium coefficient r2 ≥ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 25 of (b6) (SNP: the SNP identified by SNP ID rs13270610, the risk allele is A) is the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 26 (SNP: the SNP identified by SNP ID rs3927066, the risk allele is T), or the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 27 (SNP: the SNP identified by SNP ID rs1868862, the risk allele is A), The method according to [1], wherein the SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 28 (SNP: the SNP identified by SNP ID rs7829349, the risk allele is T) is the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 29 (SNP: the SNP identified by SNP ID rs7009044, the risk allele is T), or the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 30 (SNP: the SNP identified by SNP ID rs28545626, the risk allele is C). [4] The SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 31 (SNP: the SNP identified by SNP ID rs139889875, the risk allele is T) is the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 32 (SNP: the SNP identified by SNP ID rs117434128, the risk allele is A), The method according to [1], wherein the SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 33 (SNP: the SNP identified by SNP ID rs9995443, the risk allele is T) is the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 34 (SNP: the SNP identified by SNP ID rs2314413, the risk allele is T), or the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 35 (SNP: the SNP identified by SNP ID rs56106376, the risk allele is C). [4] The SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 36 (SNP: the SNP identified by SNP ID rs79986676, the risk allele is T) is the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 37 (SNP: the SNP identified by SNP ID rs77171220, the risk allele is A), The method according to [1], wherein an SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 38 (SNP: the SNP identified by ID rs9375677, the risk allele is T) is the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 39 (SNP: the SNP identified by ID rs17058152, the risk allele is C), or the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 40 (SNP: the SNP identified by ID rs9375676, the risk allele is C).

[0014] [5]A method for providing a composition for preventing or improving cognitive function decline to a subject according to the degree of genetic factors of the susceptibility to cognitive function decline of the subject based on the result determined by the method according to [1]. [6]A counseling method for preventing or improving cognitive function decline according to the degree of genetic factors of the susceptibility to cognitive function decline of the subject based on the result determined by the method according to [1]. [7]The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 1 (SNP: the SNP identified by ID rs11643122), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 3 (SNP: the SNP identified by ID rs2162765), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 6 (SNP: the SNP identified by ID rs3806915), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 9 (SNP: the SNP identified by ID rs12997044), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 12 (SNP: the SNP identified by ID rs9567703), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 15 (SNP: the SNP identified by ID rs17360733), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 18 (SNP: the SNP identified by ID rs1039044), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 21 (SNP: the SNP identified by SNP ID rs7782570), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 24 (SNP: the SNP identified by SNP ID rs3789002), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 25 (SNP: the SNP identified by SNP ID rs13270610), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 28 (SNP: the SNP identified by SNP ID rs7829349) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 31 (SNP: the SNP identified by SNP ID rs139889875) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 33 (SNP: the SNP identified by SNP ID rs9995443) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 36 (SNP: the SNP identified by SNP ID rs79986676) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 38 (SNP: the SNP identified by SNP ID rs9375677), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 41 (SNP: the SNP identified by SNP ID rs1106123), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 2 (SNP: the SNP identified by SNP ID rs76800139), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 4 (SNP: the SNP identified by SNP ID rs7705063), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 5 (SNP: the SNP identified by SNP ID rs2913765), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 7 (SNP: the SNP identified by SNP ID rs9327010) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 8 (SNP: the SNP identified by SNP: ID rs28489253), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 10 (SNP: the SNP identified by SNP: ID rs34355132), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 11 (SNP: the SNP identified by SNP: ID rs2287412), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 13 (SNP: the SNP identified by SNP: ID rs912435), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 14 (SNP: the SNP identified by SNP: ID rs912430), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 16 (SNP: the SNP identified by SNP: ID rs16852393), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 17 (SNP: the SNP identified by SNP: ID rs6703721), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 19 (SNP: the SNP identified by SNP: ID rs264702), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 20 (SNP: the SNP identified by SNP: ID rs35780513), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 22 (SNP: the SNP identified by SNP: ID rs79424388), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 23 (SNP: the SNP identified by SNP: ID rs1971646), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 26 (SNP: the SNP identified by SNP: ID rs3927066), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 27 (SNP: the SNP identified by SNP: ID rs1868862), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 29 (SNP: the SNP identified by SNP: ID rs7009044) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 30 (SNP: the SNP identified by SNP ID rs28545626), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 32 (SNP: the SNP identified by SNP ID rs117434128), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 34 (SNP: the SNP identified by SNP ID rs2314413), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 35 (SNP: the SNP identified by SNP ID rs56106376), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 37 (SNP: the SNP identified by SNP ID rs77171220), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 39 (SNP: the SNP identified by SNP ID rs17058152), or A probe containing a sequence of 10 bases or more containing the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 40 (SNP: the SNP identified by SNP ID rs9375676), or its complementary sequence, and / or a primer capable of amplifying a region containing any of the above SNPs, a kit for determining a genetic predisposition to cognitive function decline.

Advantages of the Invention

[0015] According to the method of the present invention, by detecting the allele of a single nucleotide polymorphism (SNP) contained in genomic DNA present in a biological sample of a subject, it is possible to accurately and simply determine the susceptibility of the subject to cognitive function decline. Therefore, based on this determination result, it becomes possible to correctly select a composition for preventing or improving cognitive function decline according to the degree of genetic predisposition to cognitive function decline of the subject, and to provide advice for preventing or improving cognitive function decline. Therefore, the present invention is useful for taking early measures for preventing and improving cognitive function decline.

Modes for Carrying Out the Invention

[0016] 1. Method for Determining Genetic Factors Prone to Cognitive Function Decline The method for determining genetic factors prone to cognitive function decline of the present invention predicts the susceptibility to cognitive function decline using a specific single nucleotide polymorphism (SNP) associated with genetic factors prone to cognitive function decline or an SNP in linkage disequilibrium with the SNP. In the present invention, "cognitive function" is defined by the American Psychiatric Association as (i) complex attention (sustained attention, divided attention, selective attention, processing speed, etc.), (ii) executive function (planning, decision-making, working memory, feedback / error correction response, habit ignoring / suppression, mental flexibility, etc.), (iii) learning and memory (sensory memory, short-term memory, long-term memory, latent learning, etc.), (iv) language (expressive language, receptive language, etc.), (v) perception-motor (visual perception, visual construction, perception-motor, execution, recognition, etc.), and (vi) social cognition (emotion recognition and theory of mind). Among them, it refers to short-term memory, working memory, and planning / execution ability.

[0017] The above-mentioned "linkage disequilibrium" means that two alleles are inherited in linkage with each other at a higher frequency than when they are inherited independently. A group of alleles showing such linkage disequilibrium is called a haplotype. In the present invention, an SNP with a linkage disequilibrium coefficient r2 of 0.8 or more, preferably 0.9 or more, more preferably 0.95 or more, and most preferably 1 can be used. SNPs in linkage disequilibrium with a specific SNP can be identified, for example, using the Ensembl Genome Browser (https: / / asia.ensembl.org / index.html) or the HapMap database (http: / / www.hapmap.org / index.html.ja). Alternatively, it can also be identified by sequencing DNA collected from multiple people (usually about 20 to 40 people) using a sequencer and searching for SNPs in linkage disequilibrium.

[0018] The method for determining the genetic predisposition to the susceptibility of cognitive function decline in the present invention includes, for a DNA-containing sample collected from a subject, detecting at least one group of alleles selected from the group consisting of alleles of one or more single nucleotide polymorphisms (SNPs) in group A below, alleles of one or more single nucleotide polymorphisms (SNPs) in group B, and alleles of one or more single nucleotide polymorphisms (SNPs) in group C, and when at least one of the bases of the detected alleles is a risk allele, determining that the subject is susceptible to cognitive function decline.

[0019] Group A is the short-term memory ability determination allele group, group B is the working memory ability determination allele group, and group C is the planning / execution ability determination allele group. In the method of the present invention, alleles of any one or two of groups A, B, and C may be the detection targets, but if alleles of all three groups are the detection targets, it is preferable because the genetic predisposition of cognitive function can be determined comprehensively and multifacetedly.

[0020] Group A (short-term memory ability determination allele group): (a1) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 1 (SNP: SNP identified by ID rs11643122, risk allele is C), or SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 1 (SNP: SNP identified by ID rs11643122, risk allele is C) and having a linkage disequilibrium coefficient r2≧0.8 (a2) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 3 (SNP: SNP identified by ID rs2162765, risk allele is C), or SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 3 (SNP: SNP identified by ID rs2162765, risk allele is C) and having a linkage disequilibrium coefficient r2≧0.8 (a3) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 6 (SNP: the SNP identified by ID rs3806915, the risk allele is C), or a SNP in linkage disequilibrium coefficient r2 ≥ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 6 (SNP: the SNP identified by ID rs3806915, the risk allele is C) (a4) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 9 (SNP: the SNP identified by ID rs12997044, the risk allele is C), or a SNP in linkage disequilibrium coefficient r2 ≥ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 9 (SNP: the SNP identified by ID rs12997044, the risk allele is C)

[0021] Examples of SNPs in linkage disequilibrium coefficient r2 ≥ 0.8 with the SNP identified by rs11643122 in (a1) above include SNPs identified by rs76800139, etc.

[0022] Examples of SNPs in linkage disequilibrium coefficient r2 ≥ 0.8 with the SNP identified by rs2162765 in (a2) above include SNPs identified by rs2913766, rs2115052, rs7705063, rs2913774, rs2973706, rs2913770, rs2913769, rs10479622, rs2913768, rs2913758, rs2913775, rs2913772, rs2913771, rs2913765, rs2860458, rs2973799, rs2973798, rs2913764, rs2913763, rs2913762, rs2973795, etc.

[0023] Examples of SNPs that are in linkage disequilibrium with an r2 ≥ 0.8 with the SNP specified by rs3806915 in (a3) above include SNPs specified by rs1027742, rs2840113, rs79671237, rs3806914, rs10068991, rs10061055, rs10062998, rs76005882, rs10053792, rs9327012, rs13360587, rs13354122, rs59351578, rs1345706, rs1345707, rs1862373, rs75750671, rs3806916, rs1862372, rs11953558, rs12719220, rs13355655, rs9327010, rs10075410, rs57497884, rs57557217, rs10045872, rs10080023, rs10066922, rs10074788, rs9327011, rs6878936, rs6897765, rs6898172, rs76468047, rs13357599, rs10070276, rs17140171, rs28489253, rs17140176, rs58364462, etc.

[0024] Examples of SNPs that are in linkage disequilibrium with an r2 ≥ 0.8 with the SNP specified by rs12997044 in (a4) above include SNPs specified by rs34355132, rs1558935, rs1073974, rs957749, rs2287412, rs4673553, rs13000755, rs4673552, etc.

[0025] Table 1 shows nucleotide sequences ([] indicates SNPs) containing the SNPs (rs11643122, rs2162765, rs3806915, rs12997044) related to the ease of decline of the above cognitive function and examples of SNPs (rs76800139, rs7705063, rs2913765, rs9327010, rs28489253, rs34355132, rs2287412) that are in linkage disequilibrium with an r2 ≥ 0.8 with these SNPs.

[0026]

Table 1

[0027] Group B (working memory ability judgment allele group): (b1) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 12 (SNP: SNP identified by ID rs9567703, risk allele is G), or SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 12 (SNP: SNP identified by ID rs9567703, risk allele is G) and in linkage disequilibrium coefficient r2≧0.8 relationship SNP (b2) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 15 (SNP: SNP identified by ID rs17360733, risk allele is A), or SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 15 (SNP: SNP identified by ID rs17360733, risk allele is A) and in linkage disequilibrium coefficient r2≧0.8 relationship SNP (b3) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 18 (SNP: SNP identified by ID rs1039044, risk allele is A), or SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 18 (SNP: SNP identified by ID rs1039044, risk allele is A) and in linkage disequilibrium coefficient r2≧0.8 relationship SNP (b4) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 21 (SNP: SNP identified by ID rs7782570, risk allele is T), or SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 21 (SNP: SNP identified by ID rs7782570, risk allele is T) and in linkage disequilibrium coefficient r2≧0.8 relationship SNP (b5) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 24 (SNP: SNP identified by ID rs3789002, risk allele is G) (b6) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 25 (SNP: the SNP identified by SNP ID rs13270610, the risk allele is A), or an SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 25 (SNP: the SNP identified by SNP ID rs13270610, the risk allele is A) (b7) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 28 (SNP: the SNP identified by SNP ID rs7829349, the risk allele is T), or an SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 28 (SNP: the SNP identified by SNP ID rs7829349, the risk allele is T)

[0028] Examples of SNPs having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP identified by rs9567703 in (b1) above include SNPs identified by rs912435, rs912430, etc.

[0029] Examples of SNPs having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP identified by rs17360733 in (b2) above include SNPs identified by rs16852397, rs79143924, rs77513168, rs74560211, rs41508450, rs75659484, rs16852393, rs6703721, etc.

[0030] Examples of SNPs having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP identified by rs1039044 in (b3) above include SNPs identified by rs264702, rs35780513, etc.

[0031] Examples of SNPs having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP identified by rs7782570 in (b4) above include SNPs identified by rs79424388, rs1971646, rs10950142, rs4318930, etc.

[0032] Examples of SNPs in linkage disequilibrium with an r2 value of 0.8 or higher with the SNP rs13270610 in (b6) above include SNPs identified by rs11995148, rs3927066, rs1868862, etc.

[0033] Examples of SNPs in linkage disequilibrium with an r2 value of 0.8 or higher with the SNP rs7829349 in (b7) above include SNPs identified by rs148237380, rs56336014, rs10099630, rs9886456, rs28671228, rs2055051, rs10103939, rs55973225, rs7823170, rs202186165, rs7009044, rs7815717, rs10089336, rs62524444, rs6996043, rs17732667, rs62524442, rs28446892, rs4358776, rs7009087, rs995939, rs28754515, rs6996947, rs7842337, rs72666140, rs62524441, rs11779785, rs16917490, rs10099677, rs28545626, rs28689135, etc.

[0034] Table 2 shows nucleotide sequences containing SNPs (the content within the brackets represents SNPs) related to the ease of decline of the above cognitive function (rs9567703, rs17360733, rs1039044, rs7782570, rs3789002, rs13270610, rs7829349) and examples of SNPs in linkage disequilibrium with an r2 value of 0.8 or higher with these SNPs (rs912435, rs912430, rs16852393, rs6703721, rs264702, rs35780513, rs79424388, rs1971646, rs3927066, rs1868862, rs7009044, rs28545626).

[0035]

Table 2

[0036] Group C (Planning and Execution Ability Judgment Allele Group): (c1) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 31 (SNP: SNP identified by ID rs139889875, risk allele is T), or SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 31 (SNP: SNP identified by ID rs139889875, risk allele is T) (c2) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 33 (SNP: SNP identified by ID rs9995443, risk allele is T), or SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 33 (SNP: SNP identified by ID rs9995443, risk allele is T) (c3) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 36 (SNP: SNP identified by ID rs79986676, risk allele is T), or SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 36 (SNP: SNP identified by ID rs79986676, risk allele is T) (c4) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 38 (SNP: SNP identified by ID rs9375677, risk allele is T), or SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 38 (SNP: SNP identified by ID rs9375677, risk allele is T) (c5) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 41 (SNP: SNP identified by ID rs1106123, risk allele is T)

[0037] Examples of SNPs in linkage disequilibrium with an r2≧0.8 relationship with the SNP rs139889875 specified in (c1) above include SNPs specified by rs117434128 etc.

[0038] Examples of SNPs in linkage disequilibrium with an r2≧0.8 relationship with the SNP rs9995443 specified in (c2) above include SNPs specified by rs2314413, rs17050352, rs56106376, rs10005351, rs60249518, rs3919615, rs17050355, rs7440907 etc.

[0039] Examples of SNPs in linkage disequilibrium with an r2≧0.8 relationship with the SNP rs79986676 specified in (c3) above include SNPs specified by rs77171220 etc.

[0040] Examples of SNPs in linkage disequilibrium with an r2≧0.8 relationship with the SNP rs9375677 specified in (c4) above include SNPs specified by rs17058152, rs7738106, rs4145782, rs9375676 etc.

[0041] Table 3 shows the nucleotide sequences ([] represents SNPs) including the SNPs (rs139889875, rs9995443, rs79986676, rs9375677, rs1106123) related to the ease of decline of the above-mentioned cognitive function and examples of SNPs in linkage disequilibrium with an r2≧0.8 relationship with the SNP (rs117434128, rs2314413, rs56106376, rs77171220, rs17058152, rs9375676).

[0042]

Table 3

[0043] As shown in the results of the following examples, the SNPs of rs11643122, rs76800139, rs2162765, rs7705063, rs2913765, rs3806915, rs9327010, rs28489253, rs12997044, rs34355132, rs2287412; rs9567703, rs912435, rs912430, rs17360733, rs16852393, rs6703721, rs1039044, rs264702, rs35780513, rs7782570, rs79424388, rs1971646, rs3789002, rs13270610, rs3927066, rs1868862, rs7829349, rs7009044, rs28545626; rs139889875, rs117434128, rs9995443, rs2314413, rs56106376, rs79986676, rs77171220, rs9375677, rs17058152, rs9375676, rs1106123 have been proven to be statistically related to the genetic factors of the susceptibility to cognitive function decline. The above SNPs can be used to determine the genetic factors of the susceptibility to cognitive function decline even if there is only one kind, but by combining two or more kinds, the determination accuracy can be improved, and the pattern types of determination can also be increased.

[0044] A single nucleotide polymorphism (SNP, hereinafter may be referred to as "SNP") generally refers to a state where the base sequence of a gene differs only at one position and the site thereof. In addition, polymorphism generally refers to two or more alleles that exist at a frequency of 1% or more in a population. The "SNP" in the present invention is an SNP registered in the SNP database (http: / / www.ncbi.nlm.nih.gov / SNP / ) of the National Center for Biotechnology Information (NCBI), which is a publicly available database that can be freely used by those skilled in the art, and can be identified by its rs number, which is the reference number.

[0045] As used herein, "allele" refers to each type having different bases that can be taken at a certain SNP site. Also, as used herein, "genotype" refers to a combination of opposing alleles at a certain SNP site. At a certain SNP site, there are three types of genotypes that are the combinations described above. A combination of the same alleles is called a homozygous type, and a combination of different alleles is called a heterozygous type. For example, for the genotype that is a combination of opposing alleles at the SNP identified by rs11643122, there are three types: A / A type, A / C type, and C / C type.

[0046] In the determination method of the present invention, "detecting an allele of a single nucleotide polymorphism (SNP)" means identifying the type of base of the allele of the SNP. The aspects of "detecting an allele of a single nucleotide polymorphism (SNP)" shall include detecting one allele of the SNP, detecting both alleles of the SNP, and identifying the genotype of the SNP.

[0047] In the determination method of the present invention, when at least one of the bases of the alleles detected by the alleles of group A is a risk allele, it is determined that the subject has a genetic predisposition to easily reduced cognitive function (short-term memory ability). For example, rs11643122 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 1) or rs7680013 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 2), which is a SNP in a linkage disequilibrium coefficient r2≧0.8 relationship with the SNP specified by rs11643122; rs2162765 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 3) or rs7705063 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 4), which is a SNP in a linkage disequilibrium coefficient r2≧0.8 relationship with the SNP specified by rs2162765; rs2913765 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 5); rs3806915 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 6) or rs9327010 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 7), which is a SNP in a linkage disequilibrium coefficient r2≧0.8 relationship with the SNP specified by rs3806915; rs28489253 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 8); rs12997044 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 9) or rs34355132 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 10), which is a SNP in a linkage disequilibrium coefficient r2≧0.8 relationship with the SNP specified by rs12997044; rs2287412 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 11). If at least one of the risk alleles shown in Table 4 below is detected, it can be determined that the cognitive function (short-term memory ability) is more likely to decline compared to the case where the risk allele is not detected. Conversely, when the risk allele is not detected, it can be determined that the cognitive function (short-term memory ability) is less likely to decline compared to the case where the risk allele is detected.

[0048] For example, in the case of the SNP identified by rs11643122, it is shown that when the genotype is the C / C type, the cognitive function is more likely to decline than when it is the A / C type or the A / A type, and when the genotype is the A / C type, the cognitive function is more likely to decline than when it is the A / A type. That is, in the order of C / C type, A / C type, and A / A type, it is shown that the cognitive function is more likely to decline. In other words, in the order of A / A type, A / C type, and C / C type, it is shown that the cognitive function is less likely to decline.

[0049]

Table 4

[0050] In the determination method of the present invention, when at least one of the bases of the alleles detected by the alleles of group B is a risk allele, it is determined that the subject has a genetic predisposition to easily reduced cognitive function (working memory ability). For example, rs9567703 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 12) or rs912435 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 13), which is a SNP having a linkage disequilibrium coefficient r2≧0.8 with the SNP identified by rs9567703, rs912430 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 14), in rs17360733 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 15) or rs16852393 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 16), which is a SNP having a linkage disequilibrium coefficient r2≧0.8 with the SNP identified by rs17360733, rs6703721 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 17), in rs1039044 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 18) or rs264702 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 19), which is a SNP having a linkage disequilibrium coefficient r2≧0.8 with the SNP identified by rs1039044, rs35780513 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 20), in rs7782570 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 21) or rs79424388 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 22), which is a SNP having a linkage disequilibrium coefficient r2≧0.8 with the SNP identified by rs7782570, rs1971646 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 23), in rs3789002 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 24), rs13270610 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 25) or a SNP having a linkage disequilibrium coefficient r2≧0.For SNPs rs3927066 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 26), rs1868862 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 27) which are in a relationship of 8, for rs7829349 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 28) or SNPs in a relationship of linkage disequilibrium coefficient r2≥0.8 with the SNP specified by rs7829349, namely rs7009044 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 29), rs28545626 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 30), if the risk allele shown in Table 5 below is detected in at least one allele, it can be determined that the cognitive function (working memory ability) is more likely to decline compared to the case where the risk allele is not detected. Conversely, if the risk allele is not detected, it can be determined that the cognitive function (working memory ability) is less likely to decline compared to the case where the risk allele is detected.

[0051] For example, in the case of the SNP specified by rs9567703, the fact that its genotype is G / G type indicates that the cognitive function is more likely to decline than when the genotype is A / G type or A / A type, and the fact that its genotype is A / G type indicates that the cognitive function is more likely to decline than when the genotype is A / A type. That is, in the order of G / G type, A / G type, A / A type, it indicates that the cognitive function is more likely to decline. In other words, in the order of A / A type, A / G type, G / G type, it indicates that the cognitive function is less likely to decline.

[0052]

Table 5

[0053] In the determination method of the present invention, when at least one of the bases of the alleles detected by the alleles of group C is a risk allele, it is determined that the subject has a genetic predisposition to easily reduced cognitive function (planning / execution ability). For example, in rs139889875 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 31) or rs117434128 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 32) which is a SNP in a linkage disequilibrium coefficient r2≧0.8 relationship with the SNP specified by rs139889875, in rs9995443 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 33) or rs2314413 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 34) which is a SNP in a linkage disequilibrium coefficient r2≧0.8 relationship with the SNP specified by rs9995443, in rs56106376 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 35), in rs79986676 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 36) or rs77171220 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 37) which is a SNP in a linkage disequilibrium coefficient r2≧0.8 relationship with the SNP specified by rs79986676, in rs9375677 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 38) or rs17058152 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 39) which is a SNP in a linkage disequilibrium coefficient r2≧0.8 relationship with the SNP specified by rs9375677, in rs9375676 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 40), in rs1106123 (SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 41), if the risk allele shown in Table 6 below is detected in at least one of the alleles, it can be determined that the cognitive function (planning / execution ability) is more likely to decline compared to the case where the risk allele is not detected. Conversely, when the risk allele is not detected, it can be determined that the cognitive function (planning / execution ability) is less likely to decline compared to the case where the risk allele is detected.

[0054] For example, in the case of the SNP identified by rs139889875, it indicates that when the genotype is the T / T type, the cognitive function is more likely to decline than when it is the G / T type or the G / G type, and when the genotype is the G / T type, it indicates that the cognitive function is more likely to decline than when it is the G / G type. That is, in the order of T / T type, G / T type, and G / G type, it indicates that the cognitive function is more likely to decline. In other words, in the order of G / G type, G / T type, and T / T type, it indicates that the cognitive function is less likely to decline.

[0055]

Table 6

[0056] In the determination method of the present invention, the race of the subject is not particularly limited, but preferably East Asians, more preferably Japanese. Here, East Asians refer to people who originate from any of the people of Japan, Korea, China, Taiwan, and Mongolia.

[0057] The DNA-containing sample used in the determination method of the present invention is not particularly limited as long as it is a biological sample containing DNA collected from a subject. The DNA contained in the DNA-containing sample is preferably genomic DNA, but when the SNP to be detected is located in a region present in mRNA other than a non-transcribed region such as a promoter or a region removed by RNA splicing such as an intron, a biological sample containing mRNA or total RNA may be used instead of genomic DNA. As the DNA-containing sample, for example, any body fluid, secretion, tissue, cell, culture of tissue or cell from which genomic DNA can be collected can be used. Specifically, saliva, blood, urine, sputum, throat swab, nasal swab, oral (buccal) mucosal swab, lacrimal gland secretion, sweat, hair, nail, skin, mucosa, tape strip peeled off after skin attachment, etc. of the subject can be mentioned. From the viewpoints of ease and low invasiveness, saliva is preferred. The sample can be collected according to the methods used in general clinical tests and prepared using known extraction methods and purification methods. At that time, a commercially available genomic DNA extraction kit can be used.

[0058] The method for detecting SNPs and determining the type of SNPs (SNP typing) is not particularly limited, and can be carried out by known methods, for example, using allele-specific primers (and probes), amplifying by PCR method or the like, and detecting polymorphisms of the amplification products by fluorescence or luminescence. For example, PCR-RFLP (restriction fragment length polymorphism) method, PCR-SSCP (single-strand conformation polymorphism) method, PCR-SSO (sequence specific oligonucleotide) method, direct sequencing method, ASO (Allele Specific Oligonucleotide) hybridization method, ASP-PCR (Allele Specific Primer-PCR) method, Snapshot method, ARMS (Amplification Refracting Mutation System) method, TaqMan PCR method, Invader method, MALDI-TOF / MS method, RNase A cleavage method, DOL (Dye-labeled Oligonucleotide Ligation) method, TDI (Template-directed Dye-terminator Incorporation), etc. can be mentioned. All of the above methods are well-known methods to those skilled in the art, and reagents and kits for determining the type of SNPs are also commercially available. For example, TaqMan SNP Genotyping Assays (manufactured by Thermo Fisher Scientific) etc. can be used.

[0059] The results obtained by the above-described determination method serve as a useful indicator for selecting a composition having a preventive and / or ameliorating effect on cognitive function decline in a subject. For example, for a subject determined to have a genetic predisposition to easily declining cognitive function, measures for preventing and / or ameliorating the decline in cognitive function can be recommended. Therefore, according to another aspect of the present invention, based on the results obtained by the above-described determination method, a composition for preventing or ameliorating cognitive function decline corresponding to the degree of the genetic predisposition to cognitive function decline in a subject is provided to the subject, a method for providing a composition for preventing or ameliorating cognitive function decline, and also a counseling method for preventing or ameliorating cognitive function decline corresponding to the degree of the genetic predisposition to cognitive function decline in a subject based on the results obtained by the above-described determination method are provided. Here, as the composition for preventing or ameliorating cognitive function decline, there are mentioned therapeutic pharmaceuticals and foods and drinks for preventing, ameliorating, or improving a disease or condition presenting a disorder of cognitive function. Examples of the disease or condition presenting a disorder of cognitive function include dementia, non-dementia cognitive impairment, memory or learning impairment, etc. Foods and drinks include, in addition to general foods and drinks, foods that can be ingested for the purpose of maintaining or promoting health other than pharmaceuticals, for example, health foods, functional foods, foods with health claims, or foods for special dietary uses. Health foods include foods provided under names such as dietary supplements, health supplements, and supplements. Foods with health claims are defined by the Food Sanitation Act or the Health Promotion Act, and include foods for specified health uses and foods with nutritional claims that can display specific health effects, functions of nutritional components, reduction of disease risks, etc., and functional display foods that can display the content reported to the Commissioner of the Consumer Affairs Agency based on scientific evidence regarding functionality. Also, foods for special dietary uses include foods for patients indicating suitability for specific subjects or patients having specific diseases, foods for the elderly, foods for caregiving, etc. Counseling for preventing or ameliorating cognitive function decline includes advice on diet (intake of antioxidants), sleep, exercise habits (walking, strolling, stretching, etc.), and intellectual behavior habits (brain training such as reading, writing, and calculation, games, etc.).

[0060] 2. Kit for Determining Genetic Predisposition to Easy Decline of Cognitive Function In the above-described SNP detection and typing methods, probes and primers corresponding to each method are used. Such probes and primers are also included in the scope of the present invention and can be provided as a kit.

[0061] Examples of the probe include a probe that contains the above SNP site and can determine the type of base at the SNP site based on the presence or absence of hybridization. Specifically, SNPs at the 101st base of the base sequences shown in SEQ ID NO: 1 (SNP: SNP identified by ID rs11643122), SNPs at the 101st base of the base sequences shown in SEQ ID NO: 3 (SNP: SNP identified by ID rs2162765), SNPs at the 101st base of the base sequences shown in SEQ ID NO: 6 (SNP: SNP identified by ID rs3806915), SNPs at the 101st base of the base sequences shown in SEQ ID NO: 9 (SNP: SNP identified by ID rs12997044), SNPs at the 101st base of the base sequences shown in SEQ ID NO: 12 (SNP: SNP identified by ID rs9567703), SNPs at the 101st base of the base sequences shown in SEQ ID NO: 15 (SNP: SNP identified by ID rs17360733), SNPs at the 101st base of the base sequences shown in SEQ ID NO: 18 (SNP: SNP identified by ID rs1039044), SNPs at the 101st base of the base sequences shown in SEQ ID NO: 21 (SNP: SNP identified by ID rs7782570), SNPs at the 101st base of the base sequences shown in SEQ ID NO: 24 (SNP: SNP identified by ID rs3789002), SNPs at the 101st base of the base sequences shown in SEQ ID NO: 25 (SNP: SNP identified by ID rs13270610), SNPs at the 101st base of the base sequences shown in SEQ ID NO: 28 (SNP: SNP identified by ID rs7829349), SNPs at the 101st base of the base sequences shown in SEQ ID NO: 31 (SNP: SNP identified by ID rs139889875), SNPs at the 101st base of the base sequences shown in SEQ ID NO: 33 (SNP: SNP identified by ID rs9995443), SNPs at the 101st base of the base sequences shown in SEQ ID NO: 36 (SNP: SNP identified by ID rs79986676), SNPs at the 101st base of the base sequences shown in SEQ ID NO: 38 (SNP: SNP identified by ID rs9375677), SNPs at the 101st base of the base sequences shown in SEQ ID NO: 41 (SNP: IDA probe having a sequence of 10 bases or more, preferably 15 bases or more or its complementary sequence, which contains the SNP specified by rs1106123, or an SNP having a linkage disequilibrium coefficient r2≧0.8 with the SNP is exemplified. The length of the probe is preferably 15 to 40 bases, more preferably 20 to 35 bases. Further, the probe may be labeled with an appropriate labeling substance. Examples of the labeling substance include enzymes (peroxidase, β-galactosidase, alkaline phosphatase, etc.), fluorescent substances (FITC, RITC, Cy3, Cy5, etc.), luminescent substances (luminol, luminol derivatives, luciferin, lucigenin, etc.), radioisotopes ( 3 H, 14 C, 32 P, 125 I, 131 I, etc.), biotin, digoxigenin, polypeptides containing a tag sequence, etc. Alternatively, a quencher (quenching substance) that absorbs the fluorescence energy emitted by the fluorescent substance may be further bound in the vicinity of the fluorescent substance.

[0062] Further, the probe may be immobilized on a solid phase (DNA array). The DNA array can simultaneously detect hybridization to each probe by hybridizing sample DNA to a large number of probes arranged on the same plane and scanning the plane. Therefore, the DNA array is useful for simultaneously analyzing a large number of SNP sites. The oligonucleotide serving as the probe mounted on the array is usually synthesized in situ. For example, in situ synthesis methods of oligonucleotides by a lithography method (Thermo Fisher Scientific), an inkjet method (Agilent), a bead array method (Illumina), etc. are known.

[0063] In addition, examples of the primer include a primer that can be used for PCR to amplify the above SNP site, or a primer that can be used for sequence analysis (sequencing) of the above SNP site. Specifically, SNPs at the 101st base of the nucleotide sequences shown in SEQ ID NO: 1 (SNP: SNP identified by ID rs11643122), SNPs at the 101st base of the nucleotide sequences shown in SEQ ID NO: 3 (SNP: SNP identified by ID rs2162765), SNPs at the 101st base of the nucleotide sequences shown in SEQ ID NO: 6 (SNP: SNP identified by ID rs3806915), SNPs at the 101st base of the nucleotide sequences shown in SEQ ID NO: 9 (SNP: SNP identified by ID rs12997044), SNPs at the 101st base of the nucleotide sequences shown in SEQ ID NO: 12 (SNP: SNP identified by ID rs9567703), SNPs at the 101st base of the nucleotide sequences shown in SEQ ID NO: 15 (SNP: SNP identified by ID rs17360733), SNPs at the 101st base of the nucleotide sequences shown in SEQ ID NO: 18 (SNP: SNP identified by ID rs1039044), SNPs at the 101st base of the nucleotide sequences shown in SEQ ID NO: 21 (SNP: SNP identified by ID rs7782570), SNPs at the 101st base of the nucleotide sequences shown in SEQ ID NO: 24 (SNP: SNP identified by ID rs3789002), SNPs at the 101st base of the nucleotide sequences shown in SEQ ID NO: 25 (SNP: SNP identified by ID rs13270610), SNPs at the 101st base of the nucleotide sequences shown in SEQ ID NO: 28 (SNP: SNP identified by ID rs7829349), SNPs at the 101st base of the nucleotide sequences shown in SEQ ID NO: 31 (SNP: SNP identified by ID rs139889875), SNPs at the 101st base of the nucleotide sequences shown in SEQ ID NO: 33 (SNP: SNP identified by ID rs9995443), SNPs at the 101st base of the nucleotide sequences shown in SEQ ID NO: 36 (SNP: SNP identified by ID rs79986676), SNPs at the 101st base of the nucleotide sequences shown in SEQ ID NO: 38 (SNP: SNP identified by IDThe SNPs identified by rs9375677, the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 41 (SNP: SNP identified by ID rs1106123), or a region containing an SNP having a linkage disequilibrium coefficient r2≧0.8 with the SNP can be amplified or sequenced. Primers that can be used for PCR to amplify the above SNP site may be oligonucleotides that can initiate complementary strand synthesis towards the SNP site using the DNA of the region containing the SNP site as a template. The length of such primers is preferably 10 to 30 bases, more preferably 15 to 25 bases. The primers can be set at positions upstream or downstream of the SNP site.

[0064] A person skilled in the art can design probes and primers according to the analysis method based on the nucleotide sequence information of the peripheral DNA region containing the SNP site. In addition, the oligonucleotides serving as probes and primers can be synthesized using a DNA automatic synthesizer usually used by methods known in the art as methods for synthesizing oligonucleotides, such as the phosphoramidite method, the H-phosphonate method, etc.

[0065] The kit of the present invention only needs to contain at least the oligonucleotides used as the above probes and primers. In addition, the kit may contain, if necessary, DNA extraction reagents, PCR reagents such as PCR buffers and DNA polymerases, detection reagents such as staining agents and electrophoresis gels, immobilization carriers, labeling substances, substrate compounds used for detecting labels, positive and negative standard samples, instructions describing the usage method of the kit, etc. The reagents in the kit may be in solution or freeze-dried.

Examples

[0066] Hereinafter, the present invention will be described more specifically by way of examples. However, the present invention is not limited thereto.

[0067] (Example 1) Identification of single nucleotide polymorphisms (SNPs) related to genetic factors of cognitive function (short-term memory ability) In conducting this study, approvals were obtained from the company's ethics review committee regarding consent forms, genotyping, etc. Samples were collected from sample providers who gave consent by signing the consent form, and genotyping and related analyses were performed.

[0068] (1) DNA sample Saliva was collected from 173 Japanese subjects aged 22 to 61 years (average age 39.0 years), and genomic DNA was extracted using the Maxwell RSC Stabilized Saliva DNA Kit (manufactured by Promega Corporation) to obtain DNA samples.

[0069] (2) SNPs analyzed Among the SNPs registered in the SNP database (http: / / www.ncbi.nlm.nih.gov / SNP / ), rs11643122, rs2162765, rs3806915, and rs12997044 were selected for analysis. Furthermore, referring to the Ensembl Genome Browser (https: / / asia.ensembl.org / index.html), SNPs in Japanese individuals that are in linkage disequilibrium with each SNP (linkage disequilibrium coefficient r2 ≥ 0.8) are shown in Table 7. Among these, rs76800139, rs7705063, rs2913765, rs9327010, rs28489253, rs34355132, and rs2287412 were also selected for analysis. In addition, rs429358 and rs11218343, which have been suggested to be related to Alzheimer's disease as comparative examples, were also analyzed together.

[0070]

Table 7

[0071] (3) Determination of genotype For the DNA sample obtained in (1), TaqMan SNP Genotyping Assays (manufactured by Applied Biosystems) and SsoAdvanced Universal Probes Supermix (manufactured by Bio Rad) were used, and the genotype was determined using a CFX384 Touch Real-Time PCR Detection System (manufactured by Bio Rad).

[0072] (4) Phenotype data (mnemonic similarity task) Cognitive function (short-term memory ability) was measured using a mnemonic similarity task. Ten images were presented in sequence on the computer screen. Each image was presented for 2,000 ms each, with a 500 ms interval between each image. After a simple task was performed for 10 minutes, new images were presented. The newly presented images were either (i) the same as the images presented previously, (ii) images presented for the first time, or (iii) images similar to the images presented previously (similar means the same type of image but flipped horizontally or with different colors). The subjects were asked to answer which of (i), (ii), or (iii) the newly presented image corresponded to. The number of correct answers and the time until the answer were measured, and (number of correct answers) / (time until the answer) was calculated and used as an index of cognitive function (short-term memory ability) (total of 10 questions).

[0073] (5) Association analysis Regarding the association between genotype data and cognitive function (short-term memory ability), multiple regression analysis was performed with phenotype data as the objective variable, the number of minor alleles of genotype data, and age as explanatory variables, and the p-value of the partial regression coefficient of the number of minor alleles was evaluated. Since 13 types of SNPs were analyzed, in order to avoid an increase in the first type of error, the significance level was corrected by the Bonferroni method (0.05 / 13), and a significant association was judged when the p-value was less than 0.0038 (3.8E-03).

[0074] (6) Results Table 8 shows the chromosome number, physical position, allele, minor allele, and bases of the risk allele, regression coefficient, and p-value for each SNP analyzed. In the column of p-values, each p-value is displayed in exponential form with base 10, and the numbers before and after the symbol E indicate the mantissa and exponent, respectively, when the p-value is expressed in exponential form.

[0075]

Table 8

[0076] As a result, rs11643122, rs2162765, rs3806915, and rs12997044 were significantly associated with the genetic predisposition of cognitive function (short-term memory ability) and were confirmed as SNPs capable of determining the cognitive function. Furthermore, since the same results were obtained for SNPs in linkage disequilibrium with each SNP, it was found that SNPs in linkage disequilibrium with rs11643122, rs2162765, rs3806915, and rs12997044 were also capable of determining cognitive function (short-term memory ability). On the other hand, no significant association was observed between rs429358 and rs11218343, which have been suggested to be associated with Alzheimer's disease, and the genetic predisposition of cognitive function.

[0077] (Example 2) Identification of Single Nucleotide Polymorphisms (SNPs) Related to the Genetic Predisposition of Cognitive Function (Working Memory Ability) In conducting this study, approvals were obtained from the company's ethics review committee regarding consent forms, genotype determination, etc. Samples were collected from sample providers who gave consent by signing the consent form, and genotype determination and related analysis were performed.

[0078] (1) DNA Samples Saliva was collected from 173 Japanese subjects aged 22 to 61 years (average age 39.0 years), and genomic DNA was extracted using the Maxwell RSC Stabilized Saliva DNA Kit (manufactured by Promega Corporation) to obtain DNA samples.

[0079] (2) Analyzed SNPs Among the SNPs registered in the SNP database (http: / / www.ncbi.nlm.nih.gov / SNP / ), rs9567703, rs17360733, rs1039044, rs7782570, rs3789002, rs13270610, and rs7829349 were selected for analysis. Furthermore, referring to the Ensembl Genome Browser (https: / / asia.ensembl.org / index.html), SNPs in Japanese individuals that are in linkage disequilibrium with each SNP (linkage disequilibrium coefficient r2 ≥ 0.8) are shown in Table 9. Among these, rs912435, rs912430, rs16852393, rs6703721, rs264702, rs35780513, rs79424388, rs1971646, rs3927066, rs1868862, rs7009044, and rs28545626 were also selected for analysis. In addition, rs429358 and rs11218343, which have been suggested to be associated with Alzheimer's disease as comparative examples, were also analyzed together.

[0080]

Table 9

[0081] (3) Genotype determination For the DNA samples obtained in (1), TaqMan SNP Genotyping Assays (manufactured by Applied Biosystems) and SsoAdvanced Universal Probes Supermix (manufactured by Bio Rad) were used, and the genotypes were determined using a CFX384 Touch Real-Time PCR Detection System (manufactured by Bio Rad).

[0082] (4) Phenotype data (N-back task) Cognitive function (working memory ability) was measured using the N-back task. Images of 3 - 5 randomly filled black 3×3 grids were presented sequentially on the computer screen. Each image was presented for 2,000 ms, with a 500 ms interval between each image. After 3 - 5 presentations, 6 new similar images were presented, and the subjects were asked to answer which image was the same as the one presented two images before. The number of correct answers and the time until answering were measured, and (number of correct answers) / (time until answering) was calculated and used as an indicator of cognitive function (working memory ability) (total 10 questions).

[0083] (5) Correlation analysis Regarding the correlation between genotype data and cognitive function (working memory ability), multiple regression analysis was performed with the phenotype data as the target variable, the number of minor alleles of the genotype data, and age as explanatory variables, and the p-value of the partial regression coefficient of the number of minor alleles was evaluated. Since 21 types of SNPs were analyzed, in order to avoid an increase in type I error, the significance level was corrected by the Bonferroni method (0.05 / 21), and a significant correlation was determined when the p-value was less than 0.0024 (2.4E - 03).

[0084] (6) Results Table 10 shows the chromosome number, physical position, allele, minor allele, and bases of the risk allele, regression coefficient, and p-value of each SNP analyzed. In the column of p-values, each p-value is displayed in exponential form with base 10, and the numbers before and after the symbol E indicate the mantissa part and the exponent part, respectively, when the p-value is expressed in exponential form.

[0085]

Table 10

[0086] As a result, rs9567703, rs17360733, rs1039044, rs7782570, rs3789002, rs13270610, and rs7829349 were significantly associated with the genetic factors of cognitive function (working memory ability) and were confirmed as SNPs capable of determining the cognitive function. Furthermore, since similar results were obtained for SNPs in linkage disequilibrium with each SNP, it was found that SNPs in linkage disequilibrium with rs9567703, rs17360733, rs1039044, rs7782570, rs13270610, and rs7829349 were also capable of determining cognitive function (working memory ability). On the other hand, no significant association was found between rs429358 and rs11218343, which have been suggested to be associated with Alzheimer's disease, and the genetic factors of cognitive function.

[0087] (Example 3) Identification of Single Nucleotide Polymorphisms (SNPs) Associated with Genetic Factors of Cognitive Function (Planning and Execution Ability) In conducting this test, approvals were obtained from the company's ethics review committee regarding consent forms, genotype determination, etc. Samples were collected from sample providers who gave consent by signing the consent form, and genotype determination and related analysis were performed.

[0088] (1) DNA Sample Saliva was collected from 173 Japanese subjects aged 22 to 61 years (average age 39.0 years), and genomic DNA was extracted using the Maxwell RSC Stabilized Saliva DNA Kit (manufactured by Promega Corporation) to obtain DNA samples.

[0089] (2) Analyzed SNPs Among the SNPs registered in the SNP database (http: / / www.ncbi.nlm.nih.gov / SNP / ), rs139889875, rs9995443, rs79986676, rs9375677, and rs1106123 were selected for analysis. Furthermore, referring to the Ensembl Genome Browser (https: / / asia.ensembl.org / index.html), SNPs (linkage disequilibrium coefficient r2 ≥ 0.8) that are in linkage disequilibrium with each SNP in Japanese are shown in Table 11. Among these, rs117434128, rs2314413, rs56106376, rs77171220, rs17058152, and rs9375676 were also selected for analysis. In addition, as comparative examples, rs429358 and rs11218343, which have been suggested to be related to Alzheimer's disease, were also analyzed together.

[0090]

Table 11

[0091] (3) Genotype determination For the DNA samples obtained in (1), TaqMan SNP Genotyping Assays (manufactured by Applied Biosystems) and SsoAdvanced Universal Probes Supermix (manufactured by Bio Rad) were used, and the genotypes were determined using a CFX384 Touch Real-Time PCR Detection System (manufactured by Bio Rad).

[0092] (4) Phenotype data (Tower of London task) Cognitive function (planning and execution ability) was measured using the Tower of London task. Two types of images (A and B) with three colored balls placed on three rods of different heights were presented. A and B were compared, and the minimum number of ball movements required to replace A with B was answered. The number of correct answers and the time until the answer were measured, and (number of correct answers) / (time until the answer) was calculated and used as an index of cognitive function (planning and execution ability) (total 10 questions).

[0093] (5) Correlation analysis Regarding the correlation between genotype data and cognitive function (planning and execution ability), multiple regression analysis was performed with phenotypic data as the target variable, the number of minor alleles of genotype data, and age as explanatory variables, and the p-value of the partial regression coefficient of the number of minor alleles was evaluated. Since 13 types of SNPs were analyzed, in order to avoid an increase in type I error, the significance level was corrected by the Bonferroni method (0.05 / 13), and it was determined that there was a significant correlation when the p-value was less than 0.0038 (3.8E-03).

[0094] (6) Results Table 12 shows the chromosome number, physical position, allele, base of the minor allele and risk allele, regression coefficient, and p-value of each SNP analyzed. In the column of p-values, each p-value is displayed in exponential form with base 10, and the numerical values before and after the symbol E indicate the mantissa part and the exponent part when the p-value is displayed in exponential form, respectively.

[0095]

Table 12

[0096] As a result, rs139889875, rs9995443, rs79986676, rs9375677, and rs1106123 were significantly associated with the genetic predisposition of cognitive function (planning and execution ability) and were confirmed as SNPs capable of determining the cognitive function. Furthermore, since similar results were obtained for SNPs in linkage disequilibrium with each SNP, it was found that SNPs in linkage disequilibrium with rs139889875, rs9995443, rs79986676, and rs9375677 were also capable of determining cognitive function (planning and execution ability). On the other hand, no significant correlation was observed between rs429358 and rs11218343, which have been suggested to be related to Alzheimer's disease, and the genetic predisposition of cognitive function.

Industrial Applicability

[0097] By the method of the present invention, it is possible to accurately and simply determine whether a subject has a genetic predisposition to cognitive function. Therefore, based on the determination result, it becomes possible to provide food and drink suitable for the subject according to the susceptibility to cognitive function decline and training for improving cognitive function, and also to conduct counseling and advice regarding a care method according to the susceptibility to cognitive function decline.

Claims

1. For a DNA-containing sample collected from a subject, a step of detecting at least one group of alleles selected from the group consisting of alleles of one or more single nucleotide polymorphisms (SNPs) in group A below, alleles of one or more single nucleotide polymorphisms (SNPs) in group B, and alleles of one or more single nucleotide polymorphisms (SNPs) in group C, and when at least one of the bases of the detected alleles is a risk allele, a step of determining that the subject is likely to have a decline in cognitive function. A method for determining a genetic factor for the likelihood of decline in cognitive function. Group A (Short-term memory ability determination allele group): (a1) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 1 (SNP identified by SNP: ID rs11643122, risk allele is C), or a SNP in a linkage disequilibrium coefficient r2≧0.8 relationship with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 1 (SNP identified by SNP: ID rs11643122, risk allele is C) (a2) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 3 (SNP identified by SNP: ID rs2162765, risk allele is C), or a SNP in a linkage disequilibrium coefficient r2≧0.8 relationship with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 3 (SNP identified by SNP: ID rs2162765, risk allele is C) (a3) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 6 (SNP identified by SNP: ID rs3806915, risk allele is C), or a SNP in a linkage disequilibrium coefficient r2≧0.8 relationship with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 6 (SNP identified by SNP: ID rs3806915, risk allele is C) (a4) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 9 (SNP identified by SNP: ID rs12997044, risk allele is C), or a SNP in a linkage disequilibrium coefficient r2≧0.8 relationship with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 9 (SNP identified by SNP: ID rs12997044, risk allele is C) Group B (Working memory ability determination allele group): (b1) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 12 (SNP: the SNP identified by SNP ID rs9567703, the risk allele is G), or an SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 12 (SNP: the SNP identified by SNP ID rs9567703, the risk allele is G) (b2) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 15 (SNP: the SNP identified by SNP ID rs17360733, the risk allele is A), or an SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 15 (SNP: the SNP identified by SNP ID rs17360733, the risk allele is A) (b3) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 18 (SNP: the SNP identified by SNP ID rs1039044, the risk allele is A), or an SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 18 (SNP: the SNP identified by SNP ID rs1039044, the risk allele is A) (b4) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 21 (SNP: the SNP identified by SNP ID rs7782570, the risk allele is T), or an SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 21 (SNP: the SNP identified by SNP ID rs7782570, the risk allele is T) (b5) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 24 (SNP: the SNP identified by SNP ID rs3789002, the risk allele is G) (b6) SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 25 (SNP: the SNP identified by SNP ID rs13270610, the risk allele is A), or an SNP having a linkage disequilibrium coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 25 (SNP: the SNP identified by SNP ID rs13270610, the risk allele is A) (b7) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 28 (SNP: the SNP identified by SNP ID rs7829349, the risk allele is T), or an SNP in linkage disequilibrium with a coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 28 (SNP: the SNP identified by SNP ID rs7829349, the risk allele is T) Group C (Planning and Execution Ability Judgment Allele Group): (c1) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 31 (SNP: the SNP identified by SNP ID rs139889875, the risk allele is T), or an SNP in linkage disequilibrium with a coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 31 (SNP: the SNP identified by SNP ID rs139889875, the risk allele is T) (c2) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 33 (SNP: the SNP identified by SNP ID rs9995443, the risk allele is T), or an SNP in linkage disequilibrium with a coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 33 (SNP: the SNP identified by SNP ID rs9995443, the risk allele is T) (c3) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 36 (SNP: the SNP identified by SNP ID rs79986676, the risk allele is T), or an SNP in linkage disequilibrium with a coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 36 (SNP: the SNP identified by SNP ID rs79986676, the risk allele is T) (c4) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 38 (SNP: the SNP identified by SNP ID rs9375677, the risk allele is T), or an SNP in linkage disequilibrium with a coefficient r2 ≧ 0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 38 (SNP: the SNP identified by SNP ID rs9375677, the risk allele is T) (c5) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 41 (SNP: the SNP identified by SNP ID rs1106123, the risk allele is T)

2. The SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 1 in (a1) (SNP: the SNP identified by SNP ID rs11643122, the risk allele is C) and having a linkage disequilibrium coefficient r2≧0.8 is the SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 2 (SNP: the SNP identified by SNP ID rs76800139, the risk allele is G). The SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 3 in (a2) (SNP: the SNP identified by SNP ID rs2162765, the risk allele is C) and having a linkage disequilibrium coefficient r2≧0.8 is the SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 4 (SNP: the SNP identified by SNP ID rs7705063, the risk allele is G), or the SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 5 (SNP: the SNP identified by SNP ID rs2913765, the risk allele is T). The SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 6 in (a3) (SNP: the SNP identified by SNP ID rs3806915, the risk allele is C) and having a linkage disequilibrium coefficient r2≧0.8 is the SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 7 (SNP: the SNP identified by SNP ID rs9327010, the risk allele is G), or the SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 8 (SNP: the SNP identified by SNP ID rs28489253, the risk allele is A). The SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 9 in (a4) (SNP: the SNP identified by SNP ID rs12997044, the risk allele is C) and having a linkage disequilibrium coefficient r2≧0.8 is the SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 10 (SNP: the SNP identified by SNP ID rs34355132, the risk allele is G), or the SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 11 (SNP: the SNP identified by SNP ID rs2287412, the risk allele is A). The method according to claim 1.

3. An SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 12 (SNP: the SNP identified by SNP ID rs9567703, the risk allele is G) and having a linkage disequilibrium coefficient r2≧0.8 is an SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 13 (SNP: the SNP identified by SNP ID rs912435, the risk allele is T), or an SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 14 (SNP: the SNP identified by SNP ID rs912430, the risk allele is G), An SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 15 (SNP: the SNP identified by SNP ID rs17360733, the risk allele is A) and having a linkage disequilibrium coefficient r2≧0.8 is an SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 16 (SNP: the SNP identified by SNP ID rs16852393, the risk allele is G), or an SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 17 (SNP: the SNP identified by SNP ID rs6703721, the risk allele is T), An SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 18 (SNP: the SNP identified by SNP ID rs1039044, the risk allele is A) and having a linkage disequilibrium coefficient r2≧0.8 is an SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 19 (SNP: the SNP identified by SNP ID rs264702, the risk allele is T), or an SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 20 (SNP: the SNP identified by SNP ID rs35780513, the risk allele is A), An SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 21 (SNP: the SNP identified by SNP ID rs7782570, the risk allele is T) and having a linkage disequilibrium coefficient r2≧0.8 is an SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 22 (SNP: the SNP identified by SNP ID rs79424388, the risk allele is G), or an SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 23 (SNP: the SNP identified by SNP ID rs1971646, the risk allele is G), An SNP that has a linkage disequilibrium coefficient r2≧0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 25 (SNP: the SNP identified by ID rs13270610, the risk allele is A) is the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 26 (SNP: the SNP identified by ID rs3927066, the risk allele is T), or the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 27 (SNP: the SNP identified by ID rs1868862, the risk allele is A), An SNP that has a linkage disequilibrium coefficient r2≧0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 28 (SNP: the SNP identified by ID rs7829349, the risk allele is T) is the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 29 (SNP: the SNP identified by ID rs7009044, the risk allele is T), or the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 30 (SNP: the SNP identified by ID rs28545626, the risk allele is C). The method according to claim 1.

4. An SNP that has a linkage disequilibrium coefficient r2≧0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 31 (SNP: the SNP identified by ID rs139889875, the risk allele is T) is the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 32 (SNP: the SNP identified by ID rs117434128, the risk allele is A), An SNP that has a linkage disequilibrium coefficient r2≧0.8 with the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 33 (SNP: the SNP identified by ID rs9995443, the risk allele is T) is the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 34 (SNP: the SNP identified by ID rs2314413, the risk allele is T), or the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 35 (SNP: the SNP identified by ID rs56106376, the risk allele is C). An SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 36 (SNP: the SNP identified by SNP: ID rs79986676, the risk allele is T) that is in linkage disequilibrium coefficient r2≥0.8 with the SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 37 (SNP: the SNP identified by SNP: ID rs77171220, the risk allele is A), An SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 38 (SNP: the SNP identified by SNP: ID rs9375677, the risk allele is T) that is in linkage disequilibrium coefficient r2≥0.8 with the SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 39 (SNP: the SNP identified by SNP: ID rs17058152, the risk allele is C), or an SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 40 (SNP: the SNP identified by SNP: ID rs9375676, the risk allele is C), the method according to claim 1.

5. A method for providing a composition for preventing or improving cognitive function decline according to the degree of genetic factor of the susceptibility to cognitive function decline of a subject, which provides the subject with a composition for preventing or improving cognitive function decline based on the result determined by the method according to claim 1.

6. A counseling method for preventing or improving cognitive function decline according to the degree of genetic factor of the susceptibility to cognitive function decline of a subject, which is based on the result determined by the method according to claim 1.

7. An SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 1 (SNP: the SNP identified by SNP: ID rs11643122), An SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 3 (SNP: the SNP identified by SNP: ID rs2162765), An SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 6 (SNP: the SNP identified by SNP: ID rs3806915), An SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 9 (SNP: the SNP identified by SNP: ID rs12997044), An SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 12 (SNP: the SNP identified by SNP: ID rs9567703), An SNP in the 101st base of the nucleotide sequence shown in SEQ ID NO: 15 (SNP: the SNP identified by SNP: ID rs17360733), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 18 (SNP: the SNP identified by SNP ID rs1039044), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 21 (SNP: the SNP identified by SNP ID rs7782570), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 24 (SNP: the SNP identified by SNP ID rs3789002), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 25 (SNP: the SNP identified by SNP ID rs13270610), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 28 (SNP: the SNP identified by SNP ID rs7829349) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 31 (SNP: the SNP identified by SNP ID rs139889875) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 33 (SNP: the SNP identified by SNP ID rs9995443) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 36 (SNP: the SNP identified by SNP ID rs79986676) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 38 (SNP: the SNP identified by SNP ID rs9375677), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 41 (SNP: the SNP identified by SNP ID rs1106123), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 2 (SNP: the SNP identified by SNP ID rs76800139), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 4 (SNP: the SNP identified by SNP ID rs7705063), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 5 (SNP: the SNP identified by SNP ID rs2913765), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 7 (SNP: the SNP identified by SNP ID rs9327010) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 8 (SNP: the SNP identified by SNP ID rs28489253), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 10 (SNP: the SNP identified by SNP ID rs34355132), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 11 (SNP: the SNP identified by SNP ID rs2287412), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 13 (SNP: the SNP identified by ID rs912435), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 14 (SNP: the SNP identified by ID rs912430), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 16 (SNP: the SNP identified by ID rs16852393), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 17 (SNP: the SNP identified by ID rs6703721), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 19 (SNP: the SNP identified by ID rs264702), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 20 (SNP: the SNP identified by ID rs35780513), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 22 (SNP: the SNP identified by ID rs79424388), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 23 (SNP: the SNP identified by ID rs1971646), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 26 (SNP: the SNP identified by ID rs3927066), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 27 (SNP: the SNP identified by ID rs1868862), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 29 (SNP: the SNP identified by ID rs7009044) The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 30 (SNP: the SNP identified by ID rs28545626), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 32 (SNP: the SNP identified by ID rs117434128), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 34 (SNP: the SNP identified by ID rs2314413), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 35 (SNP: the SNP identified by ID rs56106376), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 37 (SNP: the SNP identified by ID rs77171220), The SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 39 (SNP: the SNP identified by SNP ID rs17058152), or A probe containing a sequence of 10 bases or more containing the SNP at the 101st base of the nucleotide sequence shown in SEQ ID NO: 40 (SNP: the SNP identified by SNP ID rs9375676), or its complementary sequence, and / or a primer capable of amplifying a region containing any of the above SNPs, a kit for determining a genetic predisposition to an increased susceptibility to cognitive function decline.

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