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

基本信息

批准号：
10459545
负责人：
Yingchang Lu
金额：
$ 76.31万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10459545
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 European Evaluation Family history of Fasting Frequencies Functional disorder Gene Frequency Genes Genetic Genetic Translation 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 epidemiology 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

项目摘要

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.

项目概要/摘要冠状动脉疾病（CAD）是美国成年人死亡的主要原因。其患病率是在非洲血统的个体中最高。据估计，遗传因素占26%至69% CAD 风险的个体差异。 CAD的大规模全基因组关联研究（GWAS）主要有在欧洲和东亚血统的人群中进行，并确定了 207 个独立基因座远的。已确定的基因座很少在非洲血统的人群中得到复制。大规模遗传学研究非洲裔人群中的 CAD 缺乏。该提案将有效利用现有资源利用基因组学和流行病学联盟、百万退伍军人计划等研究人口结构建立了队列，为非洲血统人群的基因研究创造有史以来最大的样本量对 CAD 和相关心脏代谢特征进行全面表型分析。我们建议解决以下问题具体目标。目标 1 将使用混合作图、单变量 GWAS、多变量来询问基因组 GWAS 和跨种族 GWAS 方法可识别非洲血统人群中与 CAD 相关的基因座。目标 2 将使用全表型关联研究、变异性状层次聚类和综合基因组分析来表征 CAD 位点并深入了解表型、生理和机械影响是 CAD 病理生理学的基础。目标 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致病变异来确定风险变异与非洲血统人群相关的 CAD 基因综合征。人口建设—— 特定的多基因风险评分以及对罕见和低频致病变异的鉴定 CAD 基因的孟德尔综合征将有助于量化非洲血统个体的 CAD 风险并有可能缩小不同领域遗传信息临床应用的转化差距人口。已确定的 CAD 风险位点的全面跨性状关联将有助于发现 CAD 的子类型。改进遗传性 CAD 风险分类和完善 CAD 亚表型分析都将有所帮助随着精准医学在 CAD 中的实施。从新基因座阐明的新生物学见解在非洲血统人群中发现的疾病也可以推广到其他人群进行诊断， CAD 的预防和治疗。