Integrative Genomics into Genetic Association Studies of Blood Pressure and Stroke in African Americans

项目摘要 中风是非洲裔美国人（AAs）的第三大死因：他们死于中风的可能性是其他原因的两倍。 欧洲裔美国人（EAs）的中风，其发病率几乎是EAs的两倍。最近的基因组- 一项广泛的研究（GWAS）表明，非洲血统的中风风险有很大的遗传贡献 人口，遗传力估计约为35%。然而，到目前为止，遗传学研究在AA是大大滞后 尽管中风负担增加，但仍落后于EA患者。在中风的危险因素中，血压是 主要贡献者：10个AA中有4个患有高血压，比EA多50%。这些差距一直是 被认为是由环境和社会决定因素介导的，但在调整后仍然存在 人口统计学、社会经济状况、临床特征和可改变的健康行为。遗传力 一项分析表明，非洲血统与高血压有关，遗传率估计为30-40%， 收缩压和舒张压。然而，AA中高血压的遗传易感性较差 与其他民族相比。因此，有相当大的动机，以确定遗传 中风和高血压的成分。 发现易患高血压和中风的遗传变异是实现这一目标的关键一步。 了解可能导致新的预防和治疗策略的遗传机制。然而，GWAS 到目前为止，已确定的基因位点加在一起只占遗传风险的一小部分。实质性 已经致力于研究遗传变异与基因表达和其他生物学特性的关联。 通过大型合作计划，如基因型-组织表达（GTEx）和 DNA元素百科全书。这些举措加深了对职能要素的理解 在基因组中，它已被用来告知遗传关联，并确定了许多新的基因座。但是，在这方面， 这些研究中的大多数数据都集中在欧洲血统上，而很少在AA上进行。我们最近 《自然》杂志的研究表明，在一个种群中发现的基因并不容易转移到其他种群。 本研究的目的是鉴定预测各种基因组特征（基因表达， 甲基化和蛋白质），最近通过Trans-Omics for Precision收集的AA样品中 医学，CommonMind联盟和GTEx，并将这些功能信息整合到基因组中。 AA患者血压与卒中的相关性分析。深入了解分子活性和遗传变异 可以为关联分析提供信息，并使新的全基因组发现成为可能。特别是，我们建议发展 利用EA的数据来提高识别调节各种基因变异的能力的方法。 AAs中的基因组特征类型，并将基因组调控模型整合到GWAS中， 目的：确定AA患者中风风险和血压的新位点。为了实现这些目标，我们召集了 基因组研究的AA数量最多，GWAS的AA卒中病例和血压数据最多。

PROJECT SUMMARY Stroke is the third leading cause of death among African Americans (AAs): they are twice as likely to die from stroke as European Americans (EAs), and their incidence rate is almost double that of EAs. Recent genome- wide studies (GWAS) suggest there is a substantial genetic contribution to stroke risk in African ancestry populations, with heritability estimates of about 35%. However, to date, genetic studies in AAs are greatly lagging behind those in EAs despite their increased stroke burden. Among the risk factors for stroke, blood pressure is a major contributor: 4 in 10 AAs suffer from hypertension, 50% more than EAs. These disparities have been considered to be mediated by environmental and social determinants, yet they remain after adjusting for demographics, socioeconomic status, clinical characteristics, and modifiable health behaviors. Heritability analysis suggests African ancestry is associated with hypertension, with heritability estimates from 30–40% for systolic and diastolic blood pressure. However, genetic susceptibility to hypertension among AAs is less well studied compared to other ethnic groups. Therefore, there is considerable motivation for identifying the genetic components of stroke and high blood pressure in AAs. Discovery of genetic variants that predispose to blood pressure and stroke is a crucial step toward understanding genetic mechanisms that may lead to novel prevention and treatment strategies. Yet, GWAS have thus far identified genetic loci that together account for only a small proportion of the heritable risk. Substantial efforts have been devoted to studying the association of genetic variation with gene expression and other molecular characteristics through large collaborative initiatives such as Genotype-Tissue Expression (GTEx) and Encyclopedia of DNA Elements. These initiatives have provided a deeper understanding of functional elements across the genome, which have been used to inform genetic association and identified many novel loci. However, most of the data in these studies have focused on European ancestry and little has been done in AAs. Our recent work in Nature shows that genetic discoveries in one population do not readily transfer to other populations. The objective of this study is to identify variants predicting various genomic features (gene expression, methylation and protein) in AA samples that have been recently collected through Trans-Omics for Precision Medicine, the CommonMind Consortium, and GTEx, and to integrate this functional information into genetic association analysis of blood pressure and stroke in AAs. Insight into both molecular activity and genetic variation can inform association analysis and enable novel genome-wide discoveries. In particular, we propose to develop methods that leverage the data for EAs to improve power for identifying genetic variants that regulate various types of genomic features in AAs, and for integrating the genomic regulation models into GWAS with the ultimate goal to identify novel loci for stroke risk and blood pressure in AAs. To facilitate these aims we have assembled the largest number of AAs for genomic studies and AA stroke cases and blood pressure data for GWAS.