Search for the Alzheimer's Gene on Chromosome 10

寻找 10 号染色体上的阿尔茨海默病基因

• 批准号: 8423754
• 负责人: M. Ilyas Kamboh
• 金额: $ 61.97万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8423754
• 关键词: 10q11; 10q22; 10q25; Accounting; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Apolipoprotein E; Biological; Candidate Disease Gene; Cells; Choline O-Acetyltransferase; Chromosomes; Chromosomes, Human, Pair 10; Chromosomes, Human, Pair 9; Clinical; Complement; Complex; DNA Resequencing; Data; Disease; Environmental Risk Factor; Family; Gender; Genes; Genetic; Genotype; Goals; Haplotypes; Health; Human Genome; Joints; Late Onset Alzheimer Disease; Lewy Bodies; Linkage Disequilibrium; Molecular; Other Genetics; PLAU gene; Population; Predisposition; Principal Investigator; Psychotic Disorders; Public Health; Reporting; Research; Risk; Sampling; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Staging; Stratification; Testing; Universities; Urokinase; Variant; apolipoprotein E-4; apolipoprotein E-5; base; case control; cohort; density; disorder risk; follow-up; genetic association; genome-wide linkage; mental state; population based; repository; screening

DESCRIPTION (provided by principal investigator): Late-onset Alzheimer's disease (LOAD) is a complex and multifactorial disease with the possible involvement of several genes. Apolipoprotein E (APOE), especially the APOE*4 allele, has been established as a strong susceptibility marker that accounts for 20-29 percent of the risk in LOAD. In addition to the disease risk, age-at-onset (AAO) of AD is also genetically controlled and the APOE gene accounts for <10 percent of the variation in AAO. This emphasizes the involvement of other genetic and/or environmental factors, which alone or in conjunction with APOE*4, can modify the risk or AAO of AD. Recently, genomewide linkage on LOAD have provided evidence for the existence of multiple putative genes for AD on several chromosomes with the strongest evidence on chromosomes 9, 10 and 12. With the construction of a high-density map of single nucleotide polymorphisms (SNPs) in the human genome, it is now possible to use the population-based association studies approach to identify the putative AD risk genes. A broad linkage peak encompassing >65 Mb region between chromosome 10q11 (at 50 Mb) and 10q25 (at 116 Mb) that influences both AD risk and AAO has been suggested. As part of our preliminary data we have screened 21 SNPs in 13 known biological candidate genes located under this broad >65 Mb linkage region in our large case-control cohort and identified suggestive significant associations with SNPs located in the choline acetyltransferase (CHAT) gene at 50.5 Mb on 10q11 and urokinase-type plasminogen activator (PLAU) gene at 75.3 Mb on 10q22 and thus our association findings are compliment to the reported linkage studies. This provides a strong rationale to comprehensively examine this linkage region by high-powered association studies to identify the chromosome 10 AD gene. The primary goal of this application is to comprehensively examine the ~65 Mb region between 10q11 and 10q25 first screening extensive panels of linkage disequilibrium (LD)-tagging SNPs in a first stage discovery sample to identify significant SNPs (Aim 1) and then confirm the significant findings in a second stage replication sample (Aim 2). The genes harboring confirmed significant SNPs in both stage analyses will then be comprehensively screened as part of Aim 3 to identify the putative functional SNPs.

描述（由首席研究者提供）：晚期阿尔茨海默氏病（负载）是一种复杂而多因素的疾病，可能会参与几种基因。载脂蛋白E（APOE），尤其是APOE*4等位基因，已被确定为强大的敏感性标记，占负载风险的20-29％。除了疾病的风险外，AD的年龄（AAO）也受到遗传控制，APOE基因占AAO差异的10％。这强调了其他遗传和/或环境因素的参与，这些遗传和/或环境因素单独或与ApoE*4结合使用，可以改变AD的风险或AAO。最近，全基因组的载荷上的联系为在几个染色体上存在多种推定基因的证据提供了证据，这些染色体上有多种染色体上的证据9、10和12。通过建造单核苷酸多态性（SNP）的高密度图在人类基因组中的高密度图（SNP），现在可以使用基于人群的联想研究来识别Putitation Ad Implotive aD Implitative aD Implative a visitation Ad Implitation a visitation aut taterive a vistitation a vistitation aD Impact。已经提出了一个宽阔的连锁峰值，涉及10q11染色体（在50 MB）和10q25（以116 MB为单位）之间的65 MB区域影响AD风险和AAO。作为我们的初步数据的一部分，我们在我们的大病例对照组中筛选了13个已知的生物学候选基因中的21个SNP，该基因位于我们的大病例对照组中，并确定了与位于胆碱乙酰基转移酶（CHAT）基因的SNP的显着关联，该基因在50.5 MB上，在10q11和urokinase-plaistase-plaminase-plaminase-tyminase-tyminase-tyminase-tyminase-tyminase-tyminsent tyminasegator（plamins-typeator）上（ 10q22，因此我们的关联发现对报道的链接研究表示赞赏。这提供了一个有力的理由，可以通过高功率关联研究全面检查这一联系区域，以鉴定10个AD染色体基因。该应用程序的主要目标是全面检查第10q11和10q25之间的〜65 MB区域，首先筛选了广泛的链接不平衡面板（LD）在第一阶段发现样本中刻录SNP，以识别出重要的SNP（AIM 1）（AIM 1），然后在第二阶段重复样本中确认重要发现（AIM 2）。在两个阶段分析中，携带的基因确认了明显的SNP，然后将作为AIM 3的一部分进行全面筛选，以识别推定的功能SNP。