AD Gene Discovery: Exome Chip, New Endophenotypes & Functional Studies in CHARGE

AD 基因发现：外显子组芯片、新内表型

• 批准号: 8731500
• 负责人: Sudha Seshadri
• 金额: $ 26.31万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731500
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Anisotropy; Applications Grants; Atherosclerosis; Autopsy; Bioinformatics; Biological; Biological Aging; Biological Markers; Biology; Body mass index; Brain; Cardiovascular system; Cholesterol; Clinical; Code; Cognition; Cognitive; Cohort Studies; Collaborations; Communities; Computer Simulation; Coronary artery; Data; Databases; Dementia; Development; Disease; Drosophila genus; EPHA1 gene; Environment; Epidemiology; Exposure to; Framingham Heart Study; Frequencies; Funding; Generations; Genes; Genetic; Genomics; Genotype; Grant; Health; Healthcare; Heart; Heritability; Hippocampus (Brain); Human; Image; International; Intervention; Laboratories; Late Onset Alzheimer Disease; Lead; Magnetic Resonance Imaging; Measures; Memory; Messenger RNA; Meta-Analysis; Methylation; MicroRNAs; Modeling; Neurology; Neurons; Pathological Staging; Pathway interactions; Pattern; Persons; Phenotype; Plasma; Positioning Attribute; Predisposition; Prevention; Public Health; Publications; Research; Research Personnel; Resources; Risk; Risk Factors; Sampling; Serum; Staging; Testing; Translating; Variant; aged; aging brain; aging gene; brain volume; cerebral atrophy; cognitive function; cohort; cost; endophenotype; epidemiology study; exome; exome sequencing; gene discovery; gene environment interaction; gene interaction; genetic variant; genome wide association study; genome-wide; interest; middle age; novel; pre-clinical; prospective; public health relevance; sulfated glycoprotein 2; tau Proteins; working group; young adult

DESCRIPTION (provided by applicant): This competitive renewal grant application seeks to continue a collaboration that used genome-wide association data in large, prospective epidemiological cohorts, the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), with >2-6 decades of risk factor, dementia, AD, MRI and cognitive endophenotype data in >30,000 persons to identify new genes/loci underlying the risk of Alzheimer's disease (AD). It produced >50 publications, helped identify 9 novel loci for AD (BIN1 & EPHA1 first reached genome-wide significance in a CHARGE-lead publication), and 8 for AD endophenotypes. CHARGE helped found the International Genomics of Alzheimer Project (IGAP) and established collaborations with >25 cohorts/ consortia such as the Enhancing Neuro Imaging through Meta-Analysis (ENIGMA) consortium. However, genes identified to date collectively explain <35% of the observed AD heritability of 60-80%. The missing heritability could be partly explained by multiple low-frequency or rare genetic variants that can be detected cost-effectively via analysis of exome chip (EC) data now available in the original CHARGE and in 4 additional cohorts (the CHARGE-Plus sample: n=45,910, ~4058 with AD). In this application we propose the following: Aim 1: To use EC data to search for rare genetic variants related to incident clinical AD, and to AD endophenotypes. We have shown that GWAS of AD endophenotypes, e.g. hippocampal & total brain volumes, verbal memory can identify novel loci implicated in brain aging, and biological pathways underlying AD. We propose to use EC data to search for rare variants related to these established AD endophenotypes. Aim 2: To understand preclinical AD, the stage of early pathological changes 1-2 decades before clinical AD, during which AD is likely most amenable to intervention, we propose GWAS and EC analyses of emerging novel, sensitive MRI endophenotypes, cognitive and circulating biomarker (plasma ¿-amyloid and clusterin) data in the entire CHARGE-Plus and in younger cohorts aged 30-65 years. Aim 3: To better understand the biology, epidemiological and public health significance of the identified genes we will study gene-gene interactions between known and novel loci, and gene-environment interactions both targeted (interaction of loci from Aims 1&2 with midlife cholesterol and BMI), and genome-wide. The CHARGE cohorts, with premorbid data on mid-life exposure to a wide-range of environmental covariates, are uniquely positioned to study such interactions and permit analyses of other covariates when indicated. Aim 4: Finally, we will explore the biology of the identified variants using bio-informatics annotation databases created in CHARGE, available systemic and brain mRNA, miRNA, methylation data (n~8000 & 750, respectively), hippocampal neuronal expression in autopsy brains and in Drosophila tau & ¿-amyloid models. We seek modest analytic resources to leverage existing phenotypic and genotypic data worth millions, to discover new AD genes and potentially novel prevention and treatment approaches for AD.

描述（申请人提供）：这项竞争性更新资助申请旨在继续合作，在大型前瞻性流行病学队列中使用全基因组关联数据，即基因组流行病学中的心脏和衰老研究队列（CHARGE），其中>2-6年的风险因素，痴呆，AD，MRI和认知内表型数据>30，000人，以确定潜在的阿尔茨海默病（AD）风险的新基因/位点。它产生了超过50篇出版物，帮助确定了AD的9个新位点（BIN 1和EPHA 1在CHARGE领导的出版物中首次达到全基因组意义），以及AD内表型的8个。CHARGE帮助建立了国际阿尔茨海默病基因组学项目（IGAP），并与超过25个队列/联盟建立了合作关系，如通过荟萃分析增强神经成像（ENIGMA）联盟。然而，迄今为止鉴定的基因共同解释了<35%的观察到的AD遗传率60- 80%。缺失的遗传性可以部分解释为多种低频或罕见的遗传变异，这些变异可以通过分析原始CHARGE和4个额外队列中现有的外显子组芯片（EC）数据来经济有效地检测（CHARGE-Plus样本：n= 45，910，约4058例AD）。在本申请中，我们提出以下几点：目的1：使用EC数据来搜索与偶发临床AD和AD内表型相关的罕见遗传变异。我们已经表明，AD内表型的GWAS，例如海马和总脑体积，言语记忆可以识别涉及脑老化的新位点，以及AD的生物学途径。我们建议使用EC数据来搜索与这些已建立的AD内表型相关的罕见变异。目标二：为了了解临床前AD，即临床AD前1- 20年的早期病理变化阶段，在此期间AD可能最适合干预，我们提出了对整个CHARGE-Plus和年龄在30-65岁的年轻队列中新兴的新的、敏感的MRI内表型、认知和循环生物标志物（血浆淀粉样蛋白和聚集蛋白）数据进行GWAS和EC分析。目标三：为了更好地了解所鉴定基因的生物学、流行病学和公共卫生意义，我们将研究已知和新基因座之间的基因-基因相互作用，以及靶向基因-环境相互作用（目标1&2中基因座与中年胆固醇和BMI的相互作用）和全基因组。CHARGE队列具有关于中年暴露于广泛环境协变量的发病前数据，具有独特的优势来研究这种相互作用，并允许在指示时分析其他协变量。目标4：最后，我们将使用在CHARGE中创建的生物信息学注释数据库、可用的系统和脑mRNA、miRNA、甲基化数据（分别为n~8000和750）、尸检脑和果蝇tau蛋白和淀粉样蛋白模型中的海马神经元表达来探索所鉴定的变体的生物学。我们寻求适度的分析资源，以利用现有的价值数百万的表型和基因型数据，发现新的AD基因和潜在的新型AD预防和治疗方法。