Project 2: Multi-Ethnic Analysis for Alzheimer Disease

项目摘要/摘要：项目2(阿尔茨海默病的多种族分析) 阿尔茨海默病(AD)S的病因仍然相对不明，但大量证据支持强有力的 遗传成分。大多数AD基因研究都集中在欧洲(欧盟)血统的个人身上，尽管 西班牙裔/拉丁裔(HL，欧洲人、非洲人(AF)和美洲原住民(NA)血统的基因混血)和非洲人 美国人(AA，欧盟和AF血统的基因混合)有更高的AD患病率和发病率。 因此，重要的是要了解祖先如何影响不同人群中的AD风险，以便更好地提供 风险模型。总体而言，我们假设不同的人群拥有新的AD风险/保护性等位基因 它们在其他种群中很少见或不存在，或者它们具有改变共同 风险等位基因，特别是房颤和NA的祖先增加了AD的风险。ʺ招聘和留用 ADSP(ReadD-ADSP)中的阿尔茨海默病多样性遗传队列将增加新的、多样化的队列 扩大现有的基因组数据库。为了验证我们的假设，我们将在AA中执行混合映射 和HL，假设因果变异/基因更频繁地位于从 AD患病率较高的祖先人群。我们还将调查通用遗传基因座(即那些 在大多数或所有人群中授予风险)通过执行一项大型跨种族研究，其中包括AA、HL以及 欧盟和澳大利亚的祖先群体。这种方法将提高统计能力，检测罕见的变异和 群体内AD遗传结构的剖析。我们还将测试关联和/或修改 在过去可能改变AD风险的选择性事件方面，基因座不同于基因组背景。学习 AD遗传风险的多样性，我们将：1)确定AD遗传变异的AF和NA来源，使用 混合种群，并研究特定种族的修饰物。我们将估算全球和本地血统 在每个HL和AA队列中分别进行研究，以调查它们与AD的关联并确定基因组的优先顺序 房颤或NA血统较高者AD风险较高的部分。将对这些细分市场进行精细绘制 使用项目1中开发的资源，并进行祖先感知的关联测试。我们还将检查 已知或新发现的AD相关基因座的影响是否会因血统背景而改变。2)我们 将使用单标记和基因分析在AF、AA、HL、NHW队列中进行跨种族荟萃分析 基于项目1的输出，但我们还将对跨混合共享的本地祖先进行元分析 队列(例如，AA、波多黎各、古巴等地区的房颤成分)。最后，3)我们将执行显式测试 项目1和2优先选择AD相关基因座及其修改基因座，并确定是否 进化历史的模式在具有关联模式的不同种群中是一致的。

PROJECT SUMMARY/ABSTRACT: PROJECT 2 (Multi-Ethnic Analysis for Alzheimer Disease) Alzheimer's disease (AD)’s etiology is still relatively unexplained but substantial evidence supports a strong genetic component. Most AD genetic studies have focused on European (EU) descent individuals, despite Hispanic/Latinx (HL, genetically admixed of EU, African (AF) and Native American (NA) ancestry) and African Americans (AA, genetically admixed of EU and AF ancestry) having higher prevalence and incidence of AD. Thus, it is important to understand how ancestry affects AD risk among diverse populations to provide better models of risk. Overall, we hypothesize that diverse populations harbor novel AD risk/protective alleles that are rare or absent in other populations or that they have modifiers that alter the effects of common risk alleles, and specifically that AF and NA ancestries enhances AD risk. ʺRecruitment and Retention for Alzheimer’s Disease Diversity Genetic Cohorts in the ADSP (READD-ADSP) will add new, diverse cohorts that augment the existing pool of genomic data. To test our hypothesis, we will perform admixture mapping in AA and HL, assuming causal variants/genes are more frequently on chromosomal segments inherited from the ancestral population with higher AD prevalence. We will also investigate universal genetic loci (i.e. those that confer risk in most or all populations) by performing a large trans-ethnic study that includes AA, HL, as well as EU and AF ancestral populations. This approach will boost statistical power, detection of rare variant and dissection of AD genetic architecture within populations. We will also test whether associating and/or modifying loci differ from the genomic background in terms of past selective events that may have shifted AD risk. To study the diversity of AD genetic risk, we will: 1) Determine the AF and NA origins of genetic variation in AD, using admixed populations and investigate ethnic-specific modifiers. We will estimate global and local ancestry in each HL and AA cohort separately, in order to investigate their association with AD and prioritize the genomic segments where higher AF or NA ancestry confers higher AD risk. These segments will be fine-mapped employing resources developed in Project 1 and with ancestry-aware association tests. We will also examine whether the effects of known or newly-identified AD-associated loci are altered by ancestry background. 2) We will perform trans-ethnic meta-analysis across AF, AA, HL, NHW cohorts using single-marker and gene- based outputs from Project 1 but also we will meta-analyze local ancestries that are shared across admixed cohorts (e.g. AF component across AA, Puerto Ricans, Cubans etc.). Finally, 3) we will perform explicit tests of selection on AD-associated loci and their modifying loci prioritized by Project 1 and 2 and determine whether patterns of evolutionary history are consistent across diverse populations with patterns of association.