Genomic Characterization of Alzheimer's Disease Risk in the Puerto Rican Population

波多黎各人群阿尔茨海默病风险的基因组特征

• 批准号: 9194733
• 负责人: Gary Wayne Beecham
• 金额: $ 758.82万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9194733
• 关键词: Address; African; African American; Alzheimer' s Disease; Alzheimer' s disease risk; Architecture; Bioinformatics; Caribbean Hispanic; Chromosome Mapping; Collection; Communities; Custom; Data; Data Set; Disease; Dominican Republic; Elderly; European; Family; Genetic; Genetic Variation; Genetic study; Genome; Genomic approach; Genomics; Genotype; Goals; Hispanics; Individual; Island; Knowledge; Large-Scale Sequencing; Latino; Minority; Mutation; Native Americans; Not Hispanic or Latino; Participant; Pathway interactions; Phase; Population; Prevalence; Protocols documentation; Puerto Rican; Puerto Rico; Race; Resources; Risk; SNP array; Testing; Underrepresented Populations; Variant; Weight; admixture mapping; base; case control; density; follow-up; genetic epidemiology; genetic linkage analysis; genetic makeup; genetic risk factor; genetic variant; genome sequencing; identity by descent; insight; novel; prevent; protective effect; response; success; targeted treatment; therapeutic development; whole genome

PROJECT SUMMARY To identify new treatment targets, we and others have examined the genomics of Alzheimer's disease (AD). However, genomic successes so far have arisen from studying primarily non-Hispanic White (NHW) participants, and the study of minority populations has been minimal. What few studies have been done in minority populations have suggested that the genetic architectures overlap, but only partially. Thus, studying minority populations not only serves to test generalization of the NHW findings but also provides a unique opportunity for discovery of novel targets and pathways. To begin addressing these issues, we propose here the Puerto Rico Alzheimer Disease and Related Disorders Initiative (PRADI). We will whole-genome sequencing (WGS) Caribbean Hispanic Puerto Rican (CHPR) AD multiplex families to identify novel AD variation in CHPRs, and to generalize existing AD genetic discoveries to this underrepresented population. This initiative will increase our knowledge about genetic variation, particularly for the Caribbean Hispanic population of Puerto Rico (CHPR). The Puerto Rican (PR) population is the 2nd largest Hispanic/Latino population in the continental US. The prevalence of AD in the Caribbean Hispanic population of the island of PR is estimated in 65,000. The PR population is a highly mixed population with average ancestry values of ~64% European, ~21% African, and ~15% Native American. The unique genetic make-up of the PR AD population will be critical in new discovery as well in replication of findings from the Alzheimer Disease Sequencing Consortium (ADSP) CHDR data and the Alzheimer's Disease Genetics Consortium (ADGC) African American (AA) data. Thus, discovery of genetic contributions to AD risk and protective variants in CHPR would have a substantial influence on our understanding of AD and towards our goal of identifying new treatment targets. Through this proposal in response to PAR-15-356 we will address this important issue by conducting genomic studies of AD in PR. Specifically we propose a family-based study in PR that parallels the family-based efforts in the ADSP Discovery phase and that will enhance and extend both current ADSP and ADGC efforts to a broader AD community. We aim to 1) Characterize the genetic epidemiology of AD in PR 2.) Generalize and refine known risk and protective loci in familial PR AD. 3.) Perform variant discovery in our PR AD families and case control data 4.) Leverage multi-ethnic populations (PR, DR and AA) to discover novel AD risk/protective effects by calculation of local ancestry, admixture mapping and bioinformatics analysis and 4.) Perform multi-locus analyses providing insight into functional implications of the risk and protective loci. Our overall goal is to identify targets for therapeutic development that will either prevent or significantly delay the onset of AD.

项目概要 为了确定新的治疗靶点，我们和其他人检查了阿尔茨海默病的基因组学 （广告）。然而，迄今为止，基因组学的成功主要来自于对非西班牙裔白人 (NHW) 的研究 参与者，并且对少数民族人口的研究很少。哪些方面的研究很少 少数群体表明遗传结构有重叠，但只是部分重叠。因此，学习 少数民族人口不仅可以检验 NHW 研究结果的普遍性，而且还提供了一个独特的 发现新靶标和途径的机会。为了开始解决这些问题，我们在这里提出建议 波多黎各阿尔茨海默病和相关疾病倡议 (PRADI)。我们将进行全基因组 测序 (WGS) 加勒比西班牙裔波多黎各人 (CHPR) AD 多重家族以鉴定新型 AD CHPR 的变异，并将现有的 AD 遗传发现推广到这一代表性不足的人群。 这一举措将增加我们对遗传变异的了解，特别是对于加勒比西班牙裔 波多黎各人口 (CHPR)。 波多黎各人 (PR) 人口是美国大陆第二大西班牙裔/拉丁裔人口。这 据估计，加勒比海 PR 岛拉美裔人口中 AD 患病率达 65,000 人。公关 人口是一个高度混合的人口，平均血统值约为 64% 欧洲人，约 21% 非洲人， ~15% 美洲原住民。 PR AD 群体的独特基因组成对于新发现至关重要 以及重复阿尔茨海默病测序联盟 (ADSP) CHDR 数据的发现和 阿尔茨海默病遗传学联盟 (ADGC) 非裔美国人 (AA) 数据。因此，遗传基因的发现 CHPR 对 AD 风险和保护性变异的贡献将对我们产生重大影响 了解 AD 并实现我们确定新治疗目标的目标。通过这个提案 针对 PAR-15-356，我们将通过在 PR 中进行 AD 基因组研究来解决这一重要问题。 具体来说，我们建议开展一项以家庭为基础的公关研究，与 ADSP 中以家庭为基础的努力并行 发现阶段，这将增强当前 ADSP 和 ADGC 的工作并将其扩展到更广泛的 AD 社区。我们的目标是 1) 描述 PR 中 AD 的遗传流行病学特征 2.) 概括和完善已知的 家族性 PR AD 的风险和保护位点。 3.) 在我们的 PR AD 家族和病例对照中进行变异发现 数据 4.) 利用多种族人群（PR、DR 和 AA）发现新的 AD 风险/保护作用 本地血统计算、混合图谱和生物信息学分析以及 4.) 执行多位点 分析可深入了解风险和保护位点的功能影响。我们的总体目标是 确定预防或显着延缓 AD 发病的治疗开发目标。