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

摘要 这项提案的目标是创建一个研究阿尔茨海默病遗传病因学的资源 (Ad)在研究不足和服务不足的人群中。阿尔茨海默病(AD)是导致痴呆的主要原因 在老年人中发生，并在所有族裔和种族群体中发生。大多数阿尔茨海默病的遗传学研究都是 在欧洲血统的非西班牙裔白人(NHW)中表演。虽然最近的研究已经开始扩大 在其他人群中，这些人群在AD基因组学中的代表性仍然不足，特别是在病例中。一个 参与的主要障碍是缺乏对社区敏感的招聘方法，以克服 历史上对研究参与的不信任。跨人群的基因研究，特别是非裔美国人 (Aa)，在风险效应大小(例如APOE)和风险位置(例如ABCA7)上都显示出差异。进一步评估 表明遗传祖先(独立的或与环境/文化因素相互作用)可能是基础 至少是这种异质性的一部分。然而，这些努力严重不足，无法充分 描述美国非洲人(Af)和西班牙裔/拉丁裔(HL)血统的AD的遗传风险因素。饱满 定性需要包括更多的非洲血统人口。为了解决这个问题，我们 建议在此建立一个大型基因组学资源，用于研究Af和HL血统的AD。这一努力将 招募、评估、抽样和定型13,000名不同种族/民族的人，其中包括5,000名来自非洲的人， 4,000个AA和4,000个HL。临床、表型和遗传数据将与其他现有的AD基因组学相协调 努力(如阿尔茨海默病遗传学联合会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来证明这一方法的实用性和价值 资源，并开始了解AA和HL人群的遗传病因。概括地说，项目1 测试队列中的基因组和表型假设，而项目2测试基于祖先的假设 在不同人群之间。这些项目还广泛使用作为该资源的一部分生成的数据 利用ADSP后续研究(ADSP-FUS)的现有数据。通过ADSP-FUS和 相关研究我们将获取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个人，以及另外51,000名非西班牙裔白人。这些研究，连同关注的 这里生成的资源代表了一种强大的方法来了解整个AD风险，具有新的 更改效果大小的轨迹和贴图修改器轨迹。这些研究将有助于阐明泛人口 阿尔茨海默病的遗传结构，为识别药物靶点提供了基础。利用祖先的种群， 这些来自非洲的人，研究风险修饰物，不仅是解剖这些人群中的风险的核心，而且是 在AA和加勒比拉美裔(CHI)中，两者都有明显的混合。此资源将使改进的 通过精准医学进行疾病预测、预防、诊断和治疗，不仅在AA，非洲人， 和其他非洲混血人群，但所有患有AD的个体。

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.