Collaborative GWAS of Dementia, AD and related MRI and Cognitive Endophenotypes

描述（由申请人提供）：阿尔茨海默病（AD）是可遗传的，但已知的风险基因（例如APOE 54）解释了不到50%的观察到的遗传变异。原因之一可能是遗传易感人群的症状出现较晚。一种新的解决方案是评估老年人AD事件和中年人定量、可遗传、内表型的共同遗传变异。表现出与AD风险分级相关的内表型包括MRI全脑和海马体积[TBV，HV]和言语记忆测试（VM）表现。未能检测出具有中等影响的基因的其他原因包括小样本、候选基因的不正确选择以及环境因素的影响。近年来，高密度全基因组关联研究（GWAS）已经成功地实现了一种不可知的方法来识别糖尿病和冠心病等复杂疾病的常见遗传变异。心脏脆弱性研究（FHS）评估了5000多名参与者的痴呆和AD事件。自1975年和1999年以来，分别进行了认知测试和大脑MRI。其他四项大型、前瞻性、流行病学研究，即鹿特丹（RS）、心血管健康（CHS）、社区动脉粥样硬化风险（ARIC）和年龄、基因/环境易感性（AGES）研究，有关于痴呆和AD和/或AD相关内在表型的数据。所有5项研究都将在2008年获得GWAS的独立资助。因此，我们已经形成了一个跨国合作，并提出了对来自这5个发现队列的38，500名参与者的数据进行荟萃分析。随后将在5个外部样本中进行第2阶段复制（进一步提高功效的具有成本效益的方法），并研究基因-基因和基因-环境相互作用。重复样本将包括MINUS（阿尔茨海默病遗传流行病学多机构研究），ULSAM（乌普萨拉成年男性纵向研究）和TASCOG（塔斯马尼亚认知和步态）研究以及TGen和Glaxo-Smith-Kline公共数据库。我们提出了以下具体目标：目标1：揭示发现队列中常见的遗传变异，这些遗传变异是痴呆事件（1553例，17，656例处于风险中）、AD事件（1219例）、MRI（n= 10，711）和VM（n= 31，072）内表型的基础。目标二：在5个复制样本（2714例AD病例，3593例对照，1200例内表型患者）中复制250个最强SNP-性状关联，在可行时使用计算机模拟比较，并在需要时进行靶向基因分型。目的3：检测基因-基因和基因环境相互作用对15个选择的SNPs与AD和内表型的关联性的影响。我们将特别寻找与APOE 54的上位性相互作用和GEI与可改变的风险因素（如饮食，体力活动，血压和糖尿病）的相互作用。我们认为，新的AD基因的鉴定将提供有价值的见解病理生理学，并可能确定危险分层和治疗的发展的分子靶点。公共卫生相关性：我们提出一项多国合作努力，将联合收割机结合超过38，500人的遗传信息，并进行仔细的神经学随访，MRI和认知测试，以确定导致阿尔茨海默病的基因，阿尔茨海默病是痴呆症的主要原因。我们将在部分样本中确定可能的罪魁祸首基因，在其余的人中证实我们的发现，然后研究这些基因如何相互作用以及与生活方式因素的相互作用。我们相信，我们的分析将确定阿尔茨海默病风险的新基因和途径，这反过来可能会提高我们对这种疾病的理解，指导我们采取新的预防策略和治疗方法。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is heritable but known risk genes (e.g. APOE 54) explain less than 50% of the observed genetic variance. One reason may be the late onset of symptoms in genetically susceptible persons. A novel solution would be to assess the common genetic variation underlying both incident AD in older adults, and quantitative, heritable, endophenotypes in middle-aged adults. Endophenotypes that demonstrate a graded association with AD risk include MRI total brain and hippocampal volumes [TBV, HV] and performance on verbal memory tests (VM). Other causes of failure to detect genes with moderate effects include small samples, incorrect selection of candidate genes, and the impact of environmental factors. In recent years high-density genome-wide association studies (GWAS) have permitted a successful agnostic approach to the identification of common genetic variants underlying complex diseases such as diabetes and coronary heart disease. The Framingham Heart Study (FHS) has evaluated over 5000 participants for incident dementia and AD. Cognitive tests and brain MRI have been obtained since 1975 and 1999, respectively. Four other large, prospective, epidemiological studies, the Rotterdam (RS), Cardiovascular Health (CHS), Atherosclerosis Risk in Communities (ARIC) and Age, Gene/Environment Susceptibility (AGES) studies have data on incident dementia & AD and/or AD related endophenotypes. All 5 studies will have independently funded GWAS in 2008. Hence we have formed a multinational collaboration and propose a meta-analysis of data on 38,500 participants from these 5 discovery cohorts. This will be followed by Stage 2 replication in 5 external samples (a cost-effective approach to further improve power) and a study of gene-gene and gene-environment interactions. The replication samples will consist of the MIRAGE (Multi-Institutional Research in Alzheimer Genetic Epidemiology), ULSAM (Uppsala Longitudinal Study of Adult Men) and TASCOG (Tasmanian Cognition and Gait) studies and the TGen and Glaxo-Smith-Kline public databases. We propose the following specific aims: Aim 1: To uncover common genetic variation in the discovery cohorts underlying incident dementia (1553 cases, 17,656 at risk), incident AD (1219 cases), and MRI (n=10,711) and VM (n=31,072) endophenotypes. Aim 2: To replicate the 250 strongest SNP-trait associations in the 5 replication samples (2714 AD cases, 3593 controls, 1200 persons with endophenotypes) using in-silico comparisons where feasible and targeted genotyping when required. Aim 3: To examine gene-gene and gene environment interactions modifying the association of 15 selected SNPs with AD and endophenotypes. We will specifically look for epistatic interactions with APOE 54 and GEI interactions with modifiable risk factors such as diet, physical activity, blood pressure and diabetes. We submit that the identification of novel AD genes will provide valuable insights into pathophysiology, and may identify molecular targets for risk stratification and the development of therapies. PUBLIC HEALTH RELEVANCE: We propose a multinational, collaborative effort that will combine genetic information on over 38,500 persons with careful neurological follow-up, MRI and cognitive tests to identify genes causing Alzheimer's disease, the leading cause of dementia. We will identify probable culprit genes in part of the sample, confirm our findings in the remaining persons, and will then examine how these genes interact with each other and with lifestyle factors. We believe our analyses will identify new genes and pathways underlying the risk of Alzheimer's disease, and this in turn may improve our understanding of the disease guiding us to new preventive strategies and treatments.