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.

项目总结