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

将基因组学整合到非裔美国人血压和中风的遗传关联研究中

• 批准号: 10372063
• 负责人: Li Hsu
• 金额: $ 67.05万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10372063
• 关键词: African American population; African ancestry; American; Blood Pressure; Cause of Death; Characteristics; Clinical; Complex; Computer software; Data; Detection; Diastolic blood pressure; Disease; Elements; Encyclopedia of DNA Elements; Ethnic group; European; Gene Expression; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genetic study; Genome; Genomics; Genotype; Goals; Health behavior; Heritability; Hypertension; Incidence; Individual; Lead; Mediating; Methods; Methylation; Minority; Modeling; Molecular; Motivation; Nature; Pathway interactions; Population; Prevention strategy; Proteins; Proteomics; Quantitative Trait Loci; Race; Regulation; Risk; Risk Factors; Sample Size; Sampling; Socioeconomic Status; Statistical Methods; Stroke; Tissues; Trans-Omics for Precision Medicine; Variant; Work; base; demographics; ethnic diversity; genetic association; genetic variant; genome wide association study; genome-wide; genome-wide analysis; genomic locus; genomic predictors; improved; insight; novel; open source; pleiotropism; public repository; social determinants; statistics; stroke risk; trait; transcriptome sequencing; treatment strategy

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.

项目概要 中风是非裔美国人 (AA) 的第三大死因：他们死于中风的可能性是非裔美国人的两倍 中风与欧洲裔美国人（EA）一样，其发病率几乎是近期基因组中 EA 的两倍。 广泛研究（GWAS）表明，非洲血统的中风风险有很大的遗传因素 遗传力估计约为 35% 然而，迄今为止，AA 的遗传学研究严重滞后。 尽管中风负担增加，但血压仍落后于 EA 地区。 一个主要因素：十分之四的 AA 患有高血压，比 EA 多 50% 这些差异。 被认为是由环境和社会决定因素介导的，但在调整后它们仍然存在 人口统计、社会经济状况、临床特征和可改变的健康行为。 分析表明非洲血统与高血压有关，遗传力估计为 30-40% 然而，AA 人群对高血压的遗传易感性较差。 因此，有相当大的动机来鉴定遗传。 AA 中的中风和高血压的组成部分。 发现易患高血压和中风的基因变异是迈向这一目标的关键一步 然而，GWAS 已经了解了可能导致新的预防和治疗策略的遗传机制。 迄今为止，已确定的基因位点仅占重大遗传风险的一小部分。 一直致力于研究遗传变异与基因表达等方面的努力 通过基因型组织表达 (GTEx) 等大型合作项目来表征分子特征 DNA 元素百科全书。这些举措让人们对功能元素有了更深入的了解。 整个基因组，它们已被用来告知遗传关联并识别出许多新的基因座。 这些研究中的大部分数据都集中在欧洲血统上，而我们最近对 AA 的研究却很少。 《自然》杂志的研究表明，一个群体的遗传发现不容易转移到其他群体。 本研究的目的是识别预测各种基因组特征（基因表达、 最近通过 Trans-Omics for Precision 收集的 AA 样品中的甲基化和蛋白质） Medicine、CommonMind Consortium 和 GTEx，并将这些功能信息整合到遗传中 AA 中血压与中风的关联分析。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实现新的全基因组发现，我们特别建议开发。 利用 EA 数据来提高识别调节各种基因变异的能力的方法 AA 中的基因组特征类型，以及将基因组调控模型整合到 GWAS 中，并具有最终的 我们的目标是确定 AA 中中风风险和血压的新位点。 用于基因组研究的最大数量的 AA 以及用于 GWAS 的 AA 中风病例和血压数据。