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: 8579953
• 负责人: Sudha Seshadri
• 金额: $ 61.84万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8579953
• 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(由申请人提供)：这项竞争性续签拨款申请寻求继续合作，使用大型、前瞻性流行病学队列、心脏和老龄化基因组流行病学研究队列(CHARE)中的全基因组关联数据，以及&gt；30,000人中2-60年的风险因素、痴呆症、AD、MRI和认知内表型数据，以确定阿尔茨海默病(AD)风险的新基因/基因座。它出版了50份出版物，帮助确定了9个AD的新基因座(BIN1和EPHA1首次在电荷领先的出版物中达到全基因组意义)，以及8个AD的内表型。Charge帮助建立了阿尔茨海默病国际基因组学项目(IGAP)，并与25个队列/财团建立了合作关系，例如通过荟萃分析增强神经成像(Enigma)财团。然而，到目前为止发现的基因共同解释了观察到的阿尔茨海默病遗传率的35%-80%。缺失的遗传率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现有的原始Charge和4个额外队列中的外显子芯片(EC)数据来经济有效地检测到(Charge-Plus样本：n=45,910，~4058伴AD)。在这项应用中，我们提出如下建议：目的1：利用EC数据寻找与临床AD发病相关的罕见遗传变异，以及AD的内表型。我们已经证明，AD的内表型，如海马区和总的脑体积，言语记忆可以识别与脑老化有关的新的基因位点，以及AD的生物学途径。我们建议使用EC数据来寻找与这些已建立的AD内表型相关的罕见变异。目的：为了了解临床前阿尔茨海默病，这是临床阿尔茨海默病发生前1-20年的早期病变阶段，在此期间阿尔茨海默病最容易受到干预，我们建议对整个Charge-Plus和30-65岁年轻队列中新出现的敏感的MRI内表型、认知和循环生物标记物(血浆淀粉样蛋白和聚集素)数据进行GWAS和EC分析。目的3：为了更好地了解已识别基因的生物学、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，以及有针对性的基因-环境相互作用(AIMS 1和2基因座与中年胆固醇和BMI的相互作用)，以及全基因组范围的基因-环境相互作用。具有中年期间接触广泛环境协变量的患病前数据的指控队列，在研究这种相互作用和允许分析其他协变量时具有独特的地位。目的4：最后，我们将利用建立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和β-淀粉样蛋白模型中海马神经元的表达，来探索已识别的突变体的生物学特性。我们寻求适度的分析资源来利用价值数百万美元的现有表型和基因数据，以发现新的AD基因和潜在的AD新的预防和治疗方法。