Genetic Epidemiology of Cognitive Decline in an Aging Population Sample

描述（由申请人提供）：本修订申请建议更新R01 AG030146，“老龄化人口样本中认知衰退的遗传流行病学”。老年人的认知能力下降及其最严重的表现是阿尔茨海默病，这是一个巨大的公共卫生问题，预计随着老年人口群体的持续增长，这一问题将变得更加严重。我们建议在我们之前的工作的基础上，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。提出的工作为增加我们对非洲裔美国人（AAs）这些表型的理解提供了巨大的潜力。基因组和表观基因组变异的综合方法可能特别适用于比较aa和欧裔美国人（EAs）的研究结果，因为这两个种族/民族群体的平均生活经历和环境不同。表观基因组的可塑性使其成为寻找过去事件的长期痕迹的绝佳场所，例如中年或早期的社会和经验疾病风险因素，这些因素可能对理解疾病风险的种族/民族差异很重要。我们将首先对现有的基因组全关联扫描（GWAS）数据中的这些表型进行多种族荟萃分析，这些数据来自七个队列的AAs和ea，代表了AAs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，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频谱上的基因组变异类别与认知能力下降的关系。然后，我们将利用对两个双种族队列中可用的表型、转录组（RNA和miRNA）和表观基因组（DNA甲基化和H3K9Ac谱）数据的综合功能解剖，对可能的因果基因组变异及其相互联系进行综合分析。最后，我们将生成100个AA脑（50个阿尔茨海默病患者和50个对照组）的DNA甲基化谱和miRNA，以有针对性地研究DNA甲基化和miRNA在AA受试者易感位点中的作用，并将这些结果与EA受试者的结果进行比较。

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.