Project 2: Multi-Ethnic Analysis for Alzheimer Disease

项目总结/摘要：项目2（阿尔茨海默病的多种族分析） 阿尔茨海默病（AD）的病因仍然相对不明，但大量证据支持一个强有力的 遗传成分。大多数AD遗传学研究都集中在欧洲（欧盟）血统的个体，尽管 西班牙裔/拉丁裔（HL，欧盟、非洲裔（AF）和美洲原住民（NA）血统的遗传混合）和非洲裔 AD患病率和发病率较高的美国人（AA，欧盟和AF血统的遗传混合）。 因此，重要的是要了解祖先如何影响不同人群中的AD风险，以提供更好的 风险模型。总的来说，我们假设不同的人群携带新的AD风险/保护等位基因， 在其他人群中罕见或不存在，或者它们具有改变常见的 风险等位基因，特别是AF和NA祖先增加AD风险。招聘和保留 ADSP中的阿尔茨海默病多样性遗传队列（READD-ADSP）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，假设致病变异/基因更频繁地在遗传自HL的染色体片段上， AD患病率较高的祖先人群。我们还将研究普遍的遗传基因座（即那些 在大多数或所有人群中赋予风险），方法是进行一项大型跨种族研究，包括AA、HL以及 EU和AF祖先群体。这种方法将提高统计能力，检测罕见变异， 分析人群中的AD遗传结构。我们还将测试是否关联和/或修改 基因座与基因组背景不同，因为过去的选择性事件可能改变了AD风险。研究 AD遗传风险的多样性，我们将：1）确定AD遗传变异的AF和NA起源，使用 混合人群，并调查种族特异性修饰符。我们将估计全球和当地的祖先 分别在每个HL和AA队列中，以研究其与AD的相关性并优先考虑基因组 AF或NA血统越高，AD风险越高。这些部分将被精细映射 使用项目1中开发的资源，并使用祖先意识关联测试。我们亦会研究 已知或新鉴定的AD相关基因座的效应是否因祖先背景而改变。2)我们 将使用单标志物和基因对AF、AA、HL、NHW队列进行跨种族荟萃分析， 基于项目1的输出，但我们也将对混合系统中共享的本地祖先进行元分析， 队列（例如，AA、波多黎各人、古巴人等的AF组分）。最后，3）我们将执行显式测试 选择AD相关基因座及其修饰基因座，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.