Genome-wide association study of coronary artery disease in individuals of African ancestry

非洲血统个体冠状动脉疾病的全基因组关联研究

• 批准号: 10685985
• 负责人: Yingchang Lu
• 金额: $ 72.2万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685985
• 关键词: Address; Admixture; Adult; African American population; African ancestry; Architecture; Asian ancestry; Awareness; Biological; Blood Pressure; Body mass index; Cause of Death; Chromatin; Classification; Clinical; Cluster Analysis; Complement; Coronary Arteriosclerosis; Data; Data Set; Development; Diabetes Mellitus; Diagnosis; East Asian; Electronic Health Record; Epidemiology; Ethnic Origin; European; European ancestry; Evaluation; Family history of; Fasting; Frequencies; Functional disorder; Gene Frequency; Genes; Genetic; Genetic study; Genome; Genomics; Glycosylated hemoglobin A; In Vitro; Individual; Insulin; Joints; Linkage Disequilibrium; Maps; Measures; Mendelian disorder; Meta-Analysis; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome Study; Pathogenicity; Pathway Analysis; Phenotype; Physiological; Population; Population Heterogeneity; Prevalence; Prevention; Public Health; Resources; Risk; Risk Factors; Sample Size; Statistical Methods; Structure; Syndrome; Testing; Tissues; United States; Variant; Veterans; Vulnerable Populations; Waist-Hip Ratio; Work; admixture mapping; biobank; blood lipid; cardiometabolism; clinical application; clinical translation; clinically relevant; cohort; disease disparity; disorder risk; experience; fasting glucose; genetic architecture; genetic information; genetic variant; genome wide association study; genome-wide; genomic locus; high risk population; implementation facilitation; improved; in silico; insight; inter-individual variation; mortality; novel; phenome; polygenic risk score; precision medicine; programs; rare variant; risk sharing; risk variant; trait; translational genetics

PROJECT SUMMARY/ABSTRACT Coronary artery disease (CAD) is a leading cause of death among adults in the United States. Its prevalence is highest in individuals of African ancestry. It has been estimated that genetic factors account for 26% to 69% of interindividual variation in CAD risk. Large-scale genome-wide association studies (GWAS) of CAD have mainly been conducted in populations of European and East-Asian ancestries and identified 207 independent loci so far. Few of the identified loci have been replicated in populations of African ancestries. Large-scale genetic study of CAD in African-ancestry populations are lacking. This proposal will efficiently leverage the existing resources of the Population Architecture using Genomics and Epidemiology Consortium, Million Veteran Program and other established cohorts to create the largest-ever sample size for a genetic study of African-ancestry populations comprehensively phenotyped for CAD and related cardiometabolic traits. We propose to address the following Specific Aims. Aim 1 will interrogate the genome using admixture mapping, univariate GWAS, multi-variate GWAS and trans-ethnic GWAS approaches to identify loci associated with CAD in African-ancestry populations. Aim 2 will use phenome-wide association studies, variant-trait hierarchical clustering and integrative genomic analyses to characterize CAD loci and gain insights into phenotypic, physiologic, and mechanistic impacts that underlie the pathophysiology of CAD. Aim 3 will explore the public health impact and clinical relevance of CAD risk variants by constructing polygenic CAD risk scores and identifying pathogenic variants in Mendelian syndromes of CAD genes that are relevant to African-ancestry populations. The construction of population- specific polygenic risk scores and identification of rare and low-frequency pathogenic variants of large effect in Mendelian syndromes of CAD genes will facilitate quantification of CAD risk in individuals of African ancestry and potentially narrow the translational gap towards clinical use of genetic information across diverse populations. The comprehensive cross-trait associations of identified CAD risk loci will facilitate the discovery of subtypes of CAD. Both improved genetic CAD risk classifications and refined CAD sub-phenotyping would help with the implementation of precision medicine in CAD. The new biological insights elucidated from novel loci identified in African-ancestry populations may also be generalized to other populations for the diagnosis, prevention, and treatment of CAD.

项目摘要/摘要 冠状动脉疾病（CAD）是美国成年人中死亡的主要原因。它的流行是 在非洲血统中最高。据估计，遗传因素占26％至69％ CAD风险的个体变化。 CAD的大规模基因组关联研究（GWAS）主要具有 是在欧洲和东亚祖先的人群中进行的，并确定了207个独立的基因座 远的。在非洲祖先的人群中，很少有确定的基因座被复制。大规模遗传研究 缺乏非洲官员的CAD。该建议将有效利用现有资源 使用基因组学和流行病学联盟，百万退伍军人计划和其他人口架构 已建立的同类人群创建有史以来最大的样本量，以供非洲官员的遗传研究 针对CAD和相关心脏代谢性状的全面表型。我们建议解决以下内容 具体目标。 AIM 1将使用混合映射，单变量GWA，多变量来询问基因组 GWAS和跨种族GWAS的方法可以识别与非洲人种群中CAD相关的基因座。 AIM 2将使用整个现象的关联研究，变异性特征分层聚类和综合基因组 分析以表征CAD基因座并获得对表型，生理和机械影响的见解 CAD的病理生理基础。 AIM 3将探讨CAD的公共卫生影响和临床相关性 通过构建多基因CAD风险评分并识别孟德尔的病原变异来风险变体 与非洲官员相关的CAD基因综合征。人口的建设 - 特定的多基因风险评分以及稀有和低频致病性变异的鉴定 Mendelian综合征的CAD基因将有助于量化非洲血统个体的CAD风险 并有可能缩小转化差距临床对遗传信息的临床使用范围 人群。确定的CAD风险基因座的全面跨特征协会将有助于发现 CAD的亚型。改善了遗传CAD风险分类和精制的CAD子表型都将有助于 通过在CAD中实施精密医学。从新颖基因座阐明的新生物学见解 在非洲 - 公主种群中确定的人群也可能被推广到其他人群以进行诊断， 预防和治疗CAD。