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: 8030415
• 负责人: M. Ilyas Kamboh
• 金额: $ 72.91万
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8030415
• 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; Screening procedure; 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

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. PUBLIC HEALTH RELEVANCE Alzheimer's disease (AD) is a major public health problem in the U.S. because it has a long clinical course, but there is no cure. Although AD has a strong genetic basis, only a small fraction of the genetic contribution has been discovered. Genome-wide linkage studies have implicated several chromosomal regions that might harbor multiple genes for AD. This study is focused on identifying the AD gene on chromosome 10 by using a large case-control sample in the discovery sample and a family-based sample in the replication sample.

描述（由主要研究者提供）：迟发性阿尔茨海默病（LOAD）是一种复杂的多因素疾病，可能涉及多个基因。载脂蛋白E (APOE)，特别是APOE*4等位基因，已被确定为一个强易感性标记，占负载风险的20- 29%。除了疾病风险外，AD的发病年龄（AAO）也受遗传控制，APOE基因占AAO变异的< 10%。这强调了其他遗传和/或环境因素的参与，这些因素单独或与APOE*4一起可以改变AD的风险或AAO。最近，LOAD上的全基因组连锁为若干染色体上存在多个假定的AD基因提供了证据，其中最有力的证据是染色体9、10和12。随着人类基因组中单核苷酸多态性（snp）高密度图谱的构建，现在可以使用基于人群的关联研究方法来识别假定的AD风险基因。在10q11染色体（50 Mb）和10q25染色体（116 Mb）之间存在一个包括bbbb65 Mb区域的宽连锁峰，影响AD风险和AAO。作为我们初步数据的一部分，我们在我们的大型病例对照队列中筛选了13个已知的生物学候选基因中的21个snp，这些基因位于bbbb65mb宽连锁区域，并确定了与位于10q11上50.5 Mb的胆碱乙酰转移酶（CHAT）基因和10q22上75.3 Mb的尿激酶型纤溶酶原激活物（PLAU）基因的snp之间的显著关联，因此我们的关联发现是对已报道的连锁研究的补充。这为通过高强度关联研究来鉴定10号染色体AD基因全面检查这一连锁区域提供了强有力的理论依据。本应用程序的主要目标是全面检查10q11和10q25之间的~65 Mb区域，首先在第一阶段发现样本中筛选大量的连锁不平衡（LD）标记snp，以确定显著snp（目标1），然后在第二阶段复制样本中确认显著发现（目标2）。在这两个阶段的分析中，含有证实的显著snp的基因将被全面筛选，作为Aim 3的一部分，以确定假定的功能性snp。阿尔茨海默病（AD）在美国是一个主要的公共卫生问题，因为它有一个漫长的临床病程，但没有治愈方法。虽然阿尔茨海默病有很强的遗传基础，但只有一小部分遗传贡献被发现。全基因组连锁研究表明，一些染色体区域可能含有多种阿尔茨海默病基因。本研究的重点是通过在发现样本中使用大病例对照样本和在复制样本中使用基于家庭的样本来鉴定10号染色体上的AD基因。