Genome Wide associate analysis of Alzheimer's Disease

描述（由申请人提供）：全基因组关联（GWA）方法现在已经成功地用于检测疾病相关的易感基因，许多遗传复杂的疾病。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水平上检测具有小效应大小的基因。例如，2型糖尿病的易感基因比值比约为1.3，在约15,000例病例和相当数量的对照中检测到。对于AD，已经进行了初步的GWA研究，使用了1000例或更少的样本。这些研究有能力检测适度影响的基因座，但不是在其他复杂疾病的分析中通常发现的小影响基因。本应用程序的主要目标是：1)收集足够的AD病例和可比较的老年人正常对照，以检测小的影响位点；2)利用高密度基因分型平台开展GWA研究，检测导致AD易感性的小效应位点；3)使用相同的基因分型平台分析大型家族性AD收集，以便将基于家族的方法应用于AD基因发现；4)为遗传学社区提供具有良好特征的AD病例、轻度认知障碍（MCI）受试者和对照组的DNA、表型和基因型资源进行分析。病例、MCI受试者和对照将是目前由29个nia资助的阿尔茨海默病中心（ADC）研究的大约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）存放在中央数据库（国家阿尔茨海默病协调中心或NACC）中。这些受试者的DNA将储存在现有的阿尔茨海默病国家细胞储存库（NCRAD）中。第二个队列将是具有广泛表型数据和DNA的多重家族，目前可从NIMH遗传倡议库获得。本研究将利用现有的阿尔茨海默病遗传学联盟（ADGC）的基础设施来协调来自多个GWA研究的数据，用于后续对多个AD GWA研究的meta和组合分析，并为研究者提供AD GWA数据用于后续分析。

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.