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

痴呆症、AD 及相关 MRI 和认知内表型的协作 GWAS

• 批准号: 8038391
• 负责人: Sudha Seshadri
• 金额: $ 53.63万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8038391
• 关键词: Adult; Age; Age of Onset; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Atherosclerosis; Blood Pressure; Brain; Candidate Disease Gene; Cardiovascular system; Clinical; Cognition; Cognitive; Cohort Studies; Collaborations; Communities; Complex; Computer Simulation; Coronary heart disease; Data; Databases; Dementia; Development; Diabetes Mellitus; Diet; Disease; Elderly; Environment; Environmental Risk Factor; Epidemiologic Studies; Epistatic Gene; Failure; Framingham Heart Study; Functional disorder; Funding; Gait; Generations; Genes; Genetic; Genetic Determinism; Genetic Epistasis; Genetic Variation; Genotype; Health; Hippocampus (Brain); Human; Late Onset Alzheimer Disease; Lateral; Lead; Life Style; Longitudinal Studies; Macular degeneration; Magnetic Resonance Imaging; Measures; Memory; Meta-Analysis; Molecular Target; Neurologic; Parkinson Disease; Participant; Pathway interactions; Performance; Persons; Phenotype; Physical activity; Predisposition; Prevention strategy; Research; Risk; Risk Factors; SNP genotyping; Sampling; Solutions; Staging; Stratification; Stroke; Symptoms; Testing; Variant; aging gene; base; cardiovascular risk factor; clinical phenotype; cohort; cost; cost effective; density; endophenotype; follow-up; gene environment interaction; genetic epidemiology; genetic variant; genome wide association study; health economics; improved; insight; lifestyle factors; lifetime risk; men; middle age; modifiable risk; nervous system disorder; novel; novel strategies; prospective; therapy development; trait

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.

描述（由申请人提供）：阿尔茨海默氏病 (AD) 是可遗传的，但已知的风险基因（例如 APOE 54）可以解释观察到的遗传变异的不到 50%。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 事件和中年成年人定量、可遗传的内表型背后的常见遗传变异。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] 以及言语记忆测试 (VM) 的表现。未能检测到具有中等影响的基因的其他原因包括样本量小、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（GWAS）已成功采用不可知论方法来识别糖尿病和冠心病等复杂疾病背后的常见遗传变异。弗雷明汉心脏研究 (FHS) 已对 5000 多名参与者进行了痴呆症和 AD 的评估。认知测试和脑部核磁共振检查分别自 1975 年和 1999 年开始进行。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，提供了有关痴呆症和 AD 和/或 AD 的数据相关的内表型。所有 5 项研究都将在 2008 年独立资助 GWAS。因此，我们建立了跨国合作，并提出对这 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二阶段复制（进一步提高功效的经济高效方法）以及基因-基因和基因-环境相互作用的研究。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（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 和葛兰素史克公共数据库。我们提出以下具体目标： 目标 1：揭示痴呆事件（1553 例，17,656 例有风险）、AD 事件（1219 例）、MRI（n=10,711）和 VM（n= 31,072）内表型。目标 2：在可行的情况下使用计算机比较并在需要时进行有针对性的基因分型，在 5 个复制样本（2714 个 AD 病例、3593 个对照、1200 个具有内表型的人）中复制 250 个最强的 SNP 性状关联。目标 3：检查基因-基因和基因环境相互作用改变 15 个选定的 SNP 与 AD 和内表型的关联。我们将专门寻找与 APOE 54 的上位相互作用以及 GEI 与可改变的危险因素（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 基因的鉴定将为病理生理学提供有价值的见解，并可能确定风险分层和治疗开发的分子靶标。公共健康相关性：我们提出一项跨国合作计划，将超过 38,500 人的遗传信息与仔细的神经学随访、MRI 和认知测试相结合，以识别导致阿尔茨海默病（痴呆症的主要原因）的基因。我们将在部分样本中识别出可能的罪魁祸首基因，在其余人中确认我们的发现，然后检查这些基因如何相互作用以及与生活方式因素相互作用。我们相信，我们的分析将确定导致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了解，指导我们采取新的预防策略和治疗方法。