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

项目摘要 为了确定新的治疗靶点，我们和其他人对阿尔茨海默病的基因组学进行了研究 （AD）。然而，迄今为止，基因组学的成功主要来自于研究非西班牙裔白色人（NHW） 对少数民族的研究很少。有几项研究 少数群体表明，遗传结构重叠，但只是部分重叠。因此，学习 少数民族人口不仅用于测试NHW结果的推广，而且还提供了一个独特的 发现新的靶点和途径的机会。为了开始解决这些问题，我们在此建议 波多黎各阿尔茨海默病和相关疾病倡议（PRADI）。我们将全基因组 对加勒比西班牙裔波多黎各人（CHPR）AD多重家族进行测序（WGS），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。 这项倡议将增加我们对遗传变异的了解，特别是对加勒比海西班牙裔人的了解。 波多黎各人口（CHPR）。 波多黎各（PR）人口是美国大陆第二大西班牙裔/拉丁裔人口。的 在PR岛的加勒比西班牙裔人口中AD的患病率估计为65，000。公关 人口是一个高度混合的人口，平均祖先值约64%欧洲人，约21%非洲人， 15%美国原住民PRAD人群的独特遗传组成将在新发现中发挥关键作用 以及阿尔茨海默病测序联盟（ADSP）CHDR数据的结果的复制， 阿尔茨海默病遗传学联盟（ADGC）非洲裔美国人（AA）数据。因此，发现基因 CHPR中AD风险和保护性变体的贡献将对我们的研究产生重大影响。 了解AD，并朝着我们确定新治疗靶点的目标前进。通过这项提案， 针对PAR-15 - 356，我们将通过对PR中的AD进行基因组研究来解决这一重要问题。 具体来说，我们提出了一个以家庭为基础的研究，在公关平行的家庭为基础的努力，在ADSP 发现阶段，这将加强和扩展目前的ADSP和ADGC工作，以更广泛的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）概括和提炼已知的 家族性PR-AD的风险和保护位点。3.）第三章在我们的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），通过以下方式发现新的AD风险/保护作用 计算地方祖先、混合作图和生物信息学分析;以及4.）执行多轨迹 分析提供洞察风险和保护位点的功能影响。我们的总体目标是 确定预防或显著延迟AD发作的治疗开发靶点。

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.