Genetic Epidemiology of Cognitive Decline in an Aging Population Sample

描述（由申请人提供）：此修订后的申请建议更新R 01 AG 030146，“老年人群样本中认知能力下降的遗传流行病学”。老年人的认知能力下降及其最严重的表现形式-阿尔茨海默病-是一个巨大的公共卫生问题，预计随着老龄人口群体的持续增长，这些问题将变得更加严重。我们建议建立在我们以前的工作，通过综合考虑表观基因组变异和基因组变异，进一步了解这些重要和常见表型的遗传结构。拟议的工作为增加我们对非裔美国人（AAs）中这些表型的理解提供了巨大的潜力。一个综合的方法，基因组和表观基因组变异可能是特别相关的研究中比较结果之间的AA和欧洲裔美国人（EA），因为不同的平均暴露于生活经验和环境的这两个种族/民族群体。表观基因组的可塑性使其成为寻找过去事件的持久痕迹的绝佳场所，例如中年或早期的社会和经验性疾病风险因素，这些因素对理解疾病风险的种族/民族差异可能很重要。我们将首先对来自7个AA和EA队列的现有全基因组关联扫描（GWAS）数据中的这些表型进行多种族荟萃分析，这些数据代表了AA的大部分可用GWAS数据。我们将从这些队列中获得5000个AA和5000个EA的大样本的额外基因组数据，以通过询问整个人类基因组的编码和剪接变异来表征0.001-0.05频谱中的基因组变异类别与认知衰退的关系。然后，我们将收集一个全面的图片可能的因果基因组变异和它们的相互联系使用综合功能解剖的表型，转录组（RNA和miRNA），和表观基因组（DNA甲基化和H3 K9 Ac配置文件）的数据，可用于两个birthoracic队列。最后，我们将从来自这两个相同队列的100个AA脑（50个患有阿尔茨海默病和50个对照）生成DNA甲基化谱和miRNA，以进行DNA甲基化和miRNA在AA受试者的易感性基因座中的作用的靶向研究，并将这些结果与从EA受试者获得的结果进行比较。

DESCRIPTION (provided by applicant): This revised application proposes to renew R01 AG030146, "Genetic Epidemiology of Cognitive Decline in an Aging Population Sample". Cognitive decline in older age and its most severe manifestation, Alzheimer's disease, are public health problems of enormous magnitude that are projected to become much larger with the continued growth of the oldest population groups. We propose to build on our previous work to further the understanding of the genetic architecture of these important and common phenotypes through an integrated consideration of both epigenomic variation and genomic variation. The proposed work offers substantial potential for increasing our understanding of these phenotypes among African Americans (AAs). An integrated approach to genomic and epigenomic variation may be especially relevant in a study comparing results among AAs and European Americans (EAs) because of the different average exposures to life experiences and environments of these two racial/ethnic groups. The plasticity of the epigenome makes it an excellent place to search for long-lasting traces of past events such as midlife or earlier social and experiential disease risk factors that may be important to understanding racial/ethnic differences in disease risk. We will initially conduct a multi-ethnic meta-analysis of these phenotypes in existing genome wide association scan (GWAS) data from seven cohorts of AAs and EAs representing a large portion of available GWAS data for AAs. We will obtain additional genomic data for a large sample of 5000 AAs and 5000 EAs from these cohorts to characterize the relation of the class of genomic variation in the 0.001-0.05 frequency spectrum to cognitive decline by interrogation of coding and splicing variation throughout the human genome. We will then assemble a comprehensive picture of possible causal genomic variants and of their interconnections using integrated functional dissection of phenomic, transcriptomic (RNA and miRNA), and epigenomic (DNA methylation and H3K9Ac profiles) data available for two of the biracial cohorts. Finally, we will generate DNA methylation profiles and miRNA from 100 AA brains (50 with Alzheimer's disease and 50 controls) from these same two cohorts ) to perform targeted investigations of the role of DNA methylation and miRNA in susceptibility loci of AA subjects and compare these results to those obtained from EA subjects.