Genome Wide associate analysis of Alzheimer's Disease

描述（由申请人提供）：全基因组关联（GWA）方法现已成功用于检测多种遗传复杂疾病的疾病相关易感基因。在这些研究中，成功的一个关键因素是样本量足够大，以便有足够的能力在全基因组显著性水平上检测出效应量小的基因。例如，2型糖尿病，在约15，000例病例和相当数量的对照组中检测到优势比约为1.3的易感基因。对于AD，已经进行了使用1，000例或更少病例样本的初步GWA研究。这些研究有能力检测到适度的效应位点，但不能检测到在其他复杂疾病分析中通常发现的小效应基因。本申请的主要目标是：1）收集足够的AD病例和可比较的老年正常对照以检测小效应基因座; 2）使用高密度基因分型平台进行GWA研究以检测有助于AD易感性的小效应基因座; 3）使用相同的基因分型平台分析大的家族性AD集合，使得基于家族的方法可以应用于AD基因发现; 4）提供良好表征的AD病例、轻度认知受损（MCI）受试者和对照的DNA、表型和基因型资源供遗传学界分析。这些病例、MCI受试者和对照组将是目前由29个由NIA资助的阿尔茨海默病中心（ADC）研究的约16，500名受试者。这些受试者的广泛表型数据作为统一数据集（UDS）保存在中央数据库（国家阿尔茨海默病协调中心或NACC）中。这些受试者的DNA将被保存在国家阿尔茨海默病细胞库（NCRAD），这是一个现有的库。第二组将是具有广泛表型数据和DNA的多重家族，目前可从NIMH遗传学倡议库获得。本研究将利用现有阿尔茨海默病遗传学联盟（ADGC）的基础设施，协调来自多项GWA研究的数据，用于多项AD GWA研究的后续Meta和组合分析，并为研究者提供AD GWA数据用于后续分析。 公共卫生相关性：阿尔茨海默病影响美国超过500万人，每年花费联邦政府超过1000亿美元。由于我们的人口正在老龄化，到2050年，如果这种疾病仍然无法治疗，美国将有1600万人患有AD，每年花费1万亿美元。目前还没有预防AD或阻止进展的方法。因此，需要对疾病机制有更多的基础知识。

DESCRIPTION (provided by applicant): Genome-wide association (GWA) methods have now been successfully used to detect disease-related susceptibility genes numerous genetically complex disorders. In these studies, a critical element for success is that the sample size be large enough so that there is adequate power to detect genes with small effect sizes at a genome-wide significance level. As an example, type 2 diabetes, susceptibility genes with odds ratios of ~1.3 were detected with cohorts of ~15,000 cases and a comparable number of controls. For AD, preliminary GWA studies utilized samples of 1,000 cases or less have been performed. These studies have the power to detect modest effect loci but not the small effect genes typically found in the analysis of other complex disorders. The primary goals of this application are to: 1) Assemble enough AD cases and comparable elderly normal controls to detect small effect loci; 2) Perform GWA studies using a high- density genotyping platform to detect small effect loci that contribute to AD susceptibility; 3) Analyze a large familial AD collection using the same genotyping platform so that family-based methods can be applied to AD gene discovery; 4) Provide a DNA, phenotype, and genotype resource of well- characterized AD cases, mild cognitive impaired (MCI) subjects, and controls for the genetics community to analyze. The cases, MCI subjects, and controls will be the approximately 16,500 subjects currently being studied by the 29 NIA-funded Alzheimer's Disease Centers (ADC's). Extensive phenotype data as a Uniform Data Set (UDS) for these subjects is in a centralized database (National Alzheimer Coordinating Center or NACC). DNA from these subjects will be deposited in the National Cell Repository for Alzheimer's Disease (NCRAD), an existing repository. A second cohort will be multiplex families with extensive phenotype data and DNA currently available from the NIMH Genetics Initiative repository. This study will make use of the infrastructure of the existing Alzheimer's Disease Genetics Consortium (ADGC) to coordinate that data from multiple GWA studies for subsequent meta and combined analysis of multiple AD GWA studies, and to provide investigators with AD GWA data for subsequent analysis. PUBLIC HEALTH RELEVANCE: Alzheimer's disease affects over 5 million people in the US costing the Federal Government over $100 billion dollars/year. Because our population is aging, in 2050, if the disease remains untreatable, there will be 16 million people in the US with AD costing $1 trillion dollars/year. Presently there are no methods of preventing AD or halting progression. Thus, more fundamental knowledge on disease mechanism is needed.