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

描述(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(如APOE 54)解释的遗传变异不到50%。其中一个原因可能是遗传易感人群出现症状较晚。一种新的解决方案是评估老年人阿尔茨海默病发病的共同遗传变异，以及中年人定量的、可遗传的内表型。显示与AD风险分级相关的内表型包括MRI、脑和海马体总体积[TBV，HV]和言语记忆测试(Vm)。其他未能检测到影响适中的基因的原因包括样本较少、候选基因选择不正确以及环境因素的影响。近年来，高密度全基因组关联研究成功地用不可知论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。弗雷明翰心脏研究(FHS)评估了5000多名参与者的痴呆症和AD事件。认知测试和脑核磁共振分别从1975年和1999年开始进行。另外四项大型的前瞻性流行病学研究鹿特丹(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)研究都有关于痴呆症和AD和/或AD相关内表型的数据。所有5项研究都将在2008年独立资助全球气候变化研究。因此，我们形成了一个跨国合作，并建议对来自这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个外部样本中进行阶段2复制(这是进一步提高能力的经济有效的方法)，并研究基因-基因和基因-环境的相互作用。复制样本将包括MIRAGE(阿尔茨海默病遗传流行病学多机构研究)、ULSAM(成人男性Uppsala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。我们提出以下具体目标：目的1：揭示偶发痴呆(1553例，17656例高危)、偶发AD(1219例)以及MRI(n=10,711)和VM(n=31,072)内表型的共同遗传变异。目的：在5个复制样本(2714例AD患者，3593例对照，1200例内表型患者)中复制250个最强的SNP-特征关联，在可行的情况下进行电子比较，并在需要时进行目标基因分型。目的：研究基因-基因和基因环境交互作用对15个SNPs与AD和内表型关联的影响。我们将专门寻找与APOE 54的上位性交互作用，以及GEI与可修改的风险因素(如饮食、体力活动、血压和糖尿病)的交互作用。我们认为，识别新的AD基因将为病理生理学提供有价值的见解，并可能为风险分层和治疗方法的发展确定分子靶点。公共卫生相关性：我们建议开展一项多国合作努力，将超过38,500人的遗传信息与仔细的神经学随访、核磁共振和认知测试相结合，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，在其余人中证实我们的发现，然后将检查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新途径，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.