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

项目总结 为了确定新的治疗目标，我们和其他人检查了阿尔茨海默病的基因组学 (Ad)。然而，到目前为止，基因组学上的成功主要来自于对非西班牙裔白人(Nhw)的研究。 参与者，对少数群体的研究一直很少。在哪些方面做过的研究很少 少数族裔群体认为，基因结构重叠，但只是部分重叠。因此，学习 少数民族人口不仅用来检验NHW研究结果的概括性，而且还提供了一个独特的 发现新的目标和途径的机会。为了开始解决这些问题，我们在这里建议 波多黎各阿尔茨海默病及相关疾病倡议。我们将实现全基因组 测序(WGS)加勒比海拉美裔波多黎各(CHPR)AD多个家族以识别新的AD CHPR的变异，并将现有的AD基因发现推广到这一代表性不足的人群。 这一倡议将增加我们对基因变异的了解，特别是对加勒比拉美裔 波多黎各人口(CHPR)。 波多黎各(PR)人口是美国大陆第二大拉美裔/拉丁裔人口。这个 据估计，在PR岛的加勒比拉美裔人口中，阿尔茨海默病的患病率为65,000人。公关 人口是一个高度混合的人口，平均祖先价值约为~%的欧洲人，~21%的非洲人，以及 ~15%的美洲原住民。PR AD人群的独特遗传构成将在新发现中发挥关键作用 以及复制阿尔茨海默病测序联盟(ADSP)CHDR数据和 阿尔茨海默病遗传学联合会(ADGC)的非裔美国人(AA)数据。因此，基因的发现 CHPR中AD风险和保护性变异的贡献将对我们的 了解阿尔茨海默病，朝着我们确定新的治疗靶点的目标前进。通过该提案在 响应PAR-15-356，我们将通过在PR中进行AD的基因组研究来解决这一重要问题。 具体地说，我们在公关中提出了一项基于家庭的研究，与ADSP中基于家庭的努力平行 发现阶段，这将增强和扩展当前ADSP和ADGC的努力，以实现更广泛的AD 社区。我们的目标是1)在PR 2中描述AD的遗传流行病学。)概括和提炼已知知识 家族性PR AD的风险和保护基因3.)在我们的公关广告系列和病例控制中执行变体发现 数据4)利用多种族人口(PR、DR和AA)通过以下方式发现新的AD风险/保护效果 地方血统计算、混合体测绘和生物信息学分析以及4.执行多轨迹 分析提供了对风险和保护性位点的功能影响的洞察。我们的总体目标是 确定可预防或显著延缓AD发病的治疗发展目标。

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.