The Origins of Alzheimer Disease in Individuals of African Ancestry

摘要 这项提议的目的是增加我们对阿尔茨海默病(AD)风险的遗传病因学的理解 在未得到充分研究和服务的人群中。阿尔茨海默病(AD)是老年人痴呆症的主要原因 阿尔茨海默病发生在所有民族和种族群体中，但大多数AD的遗传学研究都是在非 欧洲血统的西班牙裔白人(Nhw)。AD遗传学研究中缺乏多样性是有问题的，因为 对非裔美国人(AA)的研究表明，与非裔美国人相比，他们的AD患病率更高。 已知基因座的风险效应大小(例如，APOE；ABCA7)，表明多种独特的风险模式。遗传祖先 (包括等位基因频率的变异性和调节已知和新的风险基因座的新变种)，而不是 仅仅是环境/文化因素，很可能是这种异质性的至少部分基础。只有一小部分人 在阿尔茨海默病测序项目的整个基因组序列中，来自AA的更好 要确定AD的遗传风险，需要增加非洲人(AF)的样本量 血统。为了了解AD风险的总体，我们需要阐明AD的泛群遗传结构 AD，因为它将加强我们对AD的基因型与表型关系的理解，并提供 确定可用药靶标的依据。使用祖先人口，例如来自非洲的人口，来研究风险 修饰物不仅在这些人群中至关重要，而且在所有房颤人群中也是如此 血统。我们的努力将允许通过以下方式改进疾病预测、预防、诊断和治疗 精准医学，在AA、房颤和其他房颤混合人群(例如加勒比海拉美裔)中。我们将完成 这些目标通过以下方式实现：1)为家庭扩展现有的和招募新的AA多用途家庭- 基于AD风险基因座的发现，2.)增加可用于功能研究的AA大脑的数量，3.) 确定AD遗传变异的房颤起源，4)扩展AD的基因组分析以包括 心血管表型，5)评估已知AD相关变异体的分子和基因组功能 (例如，ABCA7)以及通过该项目确定的重要变种。

ABSTRACT The goal of this proposal is to increase our understanding of the genetic etiology of Alzheimer disease (AD) risk in understudied and underserved populations. Alzheimer disease (AD) is the leading cause of dementia in the elderly and occurs in all ethnic and racial groups, but most genetic studies for AD have been performed in non- Hispanic Whites (NHW) of European ancestry. The lack of diversity in AD genetics studies is problematic as studies in African Americans (AA), who have a higher prevalence of AD compared to NHW, have differences in risk effect sizes in known loci (e.g., APOE; ABCA7), indicating multiple unique patterns of risk. Genetic ancestry (including variability in allele frequencies and novel variants modulating known and novel risk loci), as opposed to only environmental/cultural factors, likely underlies at least part of this heterogeneity. With only a small number of the whole genome sequences in the Alzheimer’s Disease Sequencing Project coming from AA, better characterization of the genetic risk for AD requires increased sample sizes for individuals of African (AF) ancestry. To understand the totality of AD risk, we need to elucidate the pan-population genetic architecture of AD as it will enhance our understanding of the genotype to phenotype relationships for AD, and provide the bases for identifying druggable targets. Using ancestral populations, such as those from Africa, to study risk modifiers is critical to dissecting risk not only in those populations but also among all populations with AF ancestry. Our efforts will allow for improved disease prediction, prevention, diagnosis, and treatment through precision medicine, in AA, AF, and other AF admixed populations (e.g. Caribbean Hispanics). We will accomplish these goals through the following: 1.) expanding existing and recruiting new AA multiplex families for family- based discovery of AD risk loci, 2.) increasing the number of available AA brains for functional studies, 3.) determining the AF origins of genetic variation in AD, 4.) Extending genomic analysis of AD to include cardiovascular phenotypes, 5.) Evaluating the molecular and genomic function of known AD associated variants (e.g., ABCA7) as well as significant variants identified through this project.