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.

项目摘要 中风是非洲裔美国人（AAS）的第三大死亡原因：他们死于死亡的可能性是 中风为欧洲人（EAS），其发病率几乎是EA的两倍。最近的基因组 - 广泛的研究（GWAS）表明，非洲血统对中风风险有实质性的遗传贡献 人口，遗传力估计约为35％。但是，迄今为止，AAS中的遗传研究很大 在EAS中的人们希望他们的中风负担增加。在中风的危险因素中，血压是 主要贡献者：十分之一的AA中有4个患有高血压，比EA高出50％。这些差异已经 被认为是由环境和社会决定者介导的，但是它们在调整后仍保持 人口统计学，社会经济状况，临床特征和可修改的健康行为。遗传力 分析表明，非洲血统与高血压有关，遗传力估计为30-40％ 收缩压和舒张压。但是，AAS中对高血压的遗传敏感性不太好 与其他族裔相比，研究员。因此，有很大的动力来识别遗传 AAS中风和高血压的成分。 发现易感血压和中风的遗传变异是迈向的关键步骤 了解可能导致新预防和治疗策略的遗传机制。但是，GWAS有 到目前为止，遗传区域仅占可遗传风险的一小部分。重大的 努力一直致力于研究遗传变异与基因表达和其他 通过大型协作计划（例如基因型 - 组织表达（GTEX）和 DNA元素的百科全书。这些举措对功能要素有了更深入的了解 在整个基因组中，这些基因组被用来为遗传关联提供信息，并确定了许多新颖的基因座。然而， 这些研究中的大多数数据都集中在欧洲血统上，而在AAS中几乎没有完成。我们最近 自然界的工作表明，一个人群中的遗传发现不容易转移到其他人群中。 这项研究的目的是确定预测各种基因组特征（基因表达，， AA样品中的甲基化和蛋白质），这些样品最近通过跨词收集了精确的 医学，千域联盟和GTEX，并将这些功能信息整合到遗传中 AAS血压和中风的关联分析。洞悉分子活性和遗传变异 可以为关联分析提供信息，并启用新的全基因组发现。特别是，我们建议开发 利用EA的数据来提高功率来识别调节各种遗传变异的方法 AAS中的基因组特征类型，并将基因组调节模型整合到GWAS中 目的是确定AAS中卒中风险和血压的新颖基因座。为了促进这些目标，我们已经组装了 GWAS的基因组研究和AA中风病例和血压数据的AA数量最多。