Project 2: Multi-Ethnic Analysis for Alzheimer Disease

项目 2：阿尔茨海默病的多种族分析

• 批准号: 10333061
• 负责人: Giuseppe Tosto
• 金额: $ 65.62万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10333061
• 关键词: Affect; African; African American; African American population; African ancestry; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Awareness; Biology; Cuban; Detection; Disease; Dissection; Ethnic group; Etiology; European; Event; Exhibits; Genes; Genetic; Genetic Risk; Genetic Variation; Genetic study; Genomic Segment; Genomics; High Prevalence; Hispanic; Hispanic Populations; Incidence; Individual; Inherited; Latinx; Linkage Disequilibrium; Maps; Meta-Analysis; Modeling; Native American Ancestry; Native Americans; Not Hispanic or Latino; Output; Pattern; Population; Population Heterogeneity; Prevalence; Puerto Rican; Recording of previous events; Research; Resources; Risk; Role; Testing; Variant; Work; admixture mapping; base; causal variant; cohort; genetic architecture; genetic risk factor; genetic variant; genome-wide; genomic data; genomic locus; multi-ethnic; novel; phenotypic data; protective allele; rare variant; recruit; risk variant; variant detection

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.

项目摘要/摘要：项目 2（阿尔茨海默病的多种族分析） 阿尔茨海默氏病 (AD) 的病因仍然相对无法解释，但大量证据支持强有力的证据 尽管大多数 AD 基因研究都集中在欧洲 (EU) 血统的个体上。 西班牙裔/拉丁裔（HL，在基因上混合了欧盟、非洲 (AF) 和美洲原住民 (NA) 血统）和非洲裔 美国人（AA，在基因上混合了 EU 和 AF 血统）的 AD 患病率和发病率较高。 因此，了解血统如何影响不同人群的 AD 风险非常重要，以便提供更好的治疗方案。 总体而言，我们渴望不同的人群拥有新的 AD 风险/保护性等位基因。 在其他人群中很少见或不存在，或者它们具有改变常见效果的修饰符 风险等位基因，特别是 AF 和 NA 血统会增加 AD 风险。 ADSP (READD-ADSP) 中的阿尔茨海默病多样性遗传队列将添加新的、多样化的队列， 为了验证我们的假设，我们将在 AA 中进行混合映射。 和 HL，假设因果变异/基因更频繁地出现在从遗传的染色体片段上 我们还将调查 AD 患病率较高的祖先群体（即那些具有较高 AD 患病率的祖先群体）。 通过进行大型跨种族研究（包括 AA、HL 以及 EU 和 AF 祖先群体的这种方法将提高统计能力、罕见变异的检测和检测。 我们还将测试是否关联和/或修改 AD 遗传结构。 就过去的选择性事件而言，基因座与基因组背景不同，这些事件可能会改变 AD 风险。 为了了解 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 我们将估计全球和当地的血统。 分别在每个 HL 和 AA 队列中，以研究它们与 AD 的关联并优先考虑基因组 较高的 AF 或 NA 血统赋予较高的 AD 风险的片段 这些片段将被精细映射。 我们还将使用项目 1 中开发的资源和祖先感知关联测试进行检查。 已知或新发现的 AD 相关位点的影响是否会因祖先背景而改变 2) 我们。 将使用单标记和基因对 AF、AA、HL、NHW 队列进行跨种族荟萃分析 基于项目 1 的输出，而且我们还将对混合群体中共享的当地祖先进行元分析 队列（例如 AA、波多黎各人、古巴人等的 AF 部分）最后，3）我们将进行明确的测试。 项目 1 和 2 优先选择的 AD 相关基因座及其修饰基因座的选择，并确定是否 不同人群的进化历史模式与关联模式是一致的。