Recruitment and Retention for Alzheimer's Disease Diversity Genetic Cohorts in the ADSP (READD-ADSP)

摘要 这项提案的目的是为研究阿尔茨海默病的遗传病因学创造一个资源 (AD)研究不足和服务不足的人群。阿尔茨海默病（Alzheimer disease，AD）是痴呆的主要病因 在老年人和发生在所有民族和种族群体。大多数AD的遗传学研究都是 在欧洲血统的非西班牙裔白人（NHW）中进行。虽然最近的研究已经开始扩大 尽管这些人群在AD基因组学中的代表性仍然不足，特别是对于病例而言。一 参与的主要障碍是缺乏对社区敏感的征聘办法， 历史上对研究参与的不信任。跨人群的遗传研究，特别是非洲裔美国人 (AA)已经显示出风险效应大小的差异（例如，APOE）和风险基因座（例如，ABCA 7）。进一步评价 表明遗传祖先（独立或与环境/文化因素相互作用）可能是 至少是部分的异质性。然而，这些努力的力度远远不够， 描述美国非裔（Af）和西班牙裔/拉丁裔（HL）人群中AD的遗传风险因素。充分 表征需要包括非洲遗传祖先的额外群体。为了解决这个问题，我们 在此建议创建一个大型基因组学资源，用于研究Af和HL的AD。这一努力将 招募、评估、采样和基因分型13，000个不同种族/民族的个体，包括来自非洲的5，000人， 4,000 AA和4,000 HL。临床、表型和遗传数据将与其他现有的AD基因组学协调一致 努力（如阿尔茨海默病遗传学联盟和阿尔茨海默病测序项目; ADSP）。此外，我们还包括两个基于假设的项目，以证明这一点的效用和价值。 资源，并开始了解AA和HL人群的遗传病因。总体而言，项目1 在队列中测试基因组和表型假设，而项目2测试基于祖先的假设 在人群中。这些项目也广泛使用作为该资源的一部分生成的数据 利用ADSP随访研究（ADSP-FUS）的现有数据。通过ADSP-FUS和 我们将访问来自13，100名非洲血统个体的现有基因组病例和对照数据， 15，900名HL个体，以及另外51，000名非西班牙裔白人。这些研究，以及重点 这里生成的资源，代表了了解AD风险整体的强大方法， 基因座和改变效应大小的映射修饰基因座。这些研究将有助于阐明泛人群 AD的遗传结构，并为鉴定药物靶点提供基础。利用祖先群体， 例如来自非洲的人，研究风险修饰因子不仅是剖析这些人群的风险， 在AA和加勒比海西班牙裔（CHI）中，两者都有显著的混合。这一资源将有助于改善 通过精准医学进行疾病预测、预防、诊断和治疗，不仅在非洲， 和其他非洲混合人群，但所有的人与AD。

ABSTRACT The goal of this proposal is to create a resource for studying the genetic etiology of Alzheimer disease (AD) 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. The majority of genetic studies for AD have been performed in non-Hispanic Whites (NHW) of European ancestry. While recent studies have begun expanding into other populations, these populations are still under-represented in AD genomics, particularly for cases. A major barrier to participation has been a lack of community-sensitive recruitment approaches that overcome historical mistrust of research participation. Genetic studies across populations, in particular African Americans (AA), have shown differences in both risk effect size (e.g., APOE) and risk loci (e.g., ABCA7). Further evaluation suggests that genetic ancestry (independently or interacting with environmental/cultural factors) likely underlies at least part of this heterogeneity. However, these efforts have been significantly underpowered to fully characterize genetic risk factors of AD in US individuals of African (Af) and Hispanic/Latinx (HL) Ancestry. Full characterization requires inclusion of additional populations of African genetic ancestry. To address this, we propose here the creation of a large genomics resource for the study of AD in Af and HL Ancestry. This effort will recruit, assess, sample, and genotype 13,000 individuals of diverse race/ethnicity, including 5,000 from Africa, 4,000 AA, and 4,000 HL. Clinical, phenotypic, and genetic data will be harmonized to other existing AD genomics efforts (such as the Alzheimer Disease Genetics Consortium and the Alzheimer Disease Sequencing Project; ADSP). Furthermore, we include two hypothesis-based Projects to demonstrate the utility and value of this resource and begin understanding the genetic etiology of AA and HL populations. Broadly speaking, Project 1 tests genomic and phenotypic hypotheses within cohorts, while Project 2 tests ancestry-based hypotheses across populations. These projects make extensive use of the data generated as part of this resource, as well as taking advantage of existing data from the ADSP Follow-up Study (ADSP-FUS). Through the ADSP-FUS and related studies we will access existing genomic case and control data from 13,100 African ancestry individuals, 15,900 HL individuals, and an additional 51,000 non-Hispanic whites. These studies, together with the focused resource being generated here, represent a powerful approach to understanding the totality of AD risk, with new loci and the mapping modifier loci that alter effect sizes. These studies will help illuminate the pan-population genetic architecture of AD and provide the basis for identifying druggable targets. Using ancestral populations, such those from Africa, to study risk modifiers is central to dissecting risk not only in those populations but also among AA and Caribbean Hispanics (CHI), both with significant admixture. This resource will enable improved disease prediction, prevention, diagnosis, and treatment through precision medicine, not only in in AA, Africans, and other African admixed populations, but all individuals with AD.