A Genome-Wide Association Study in Essential Hypertension (FEHGAS2)

描述(申请人提供)：尽管对血压(BP)生理学的研究已有数十年，但我们对临床高血压(HTN)的生物学基础仍缺乏了解。最近，对大约70,000名欧洲血统的个体进行的全基因组关联研究已经成功地确定了29个基因座上的常见变异，这些变异解释了收缩压(SBP)和舒张压(DBP)2.5%的个体间差异，并伴随着HTN的影响。使用脉搏(PP)和平均动脉压(MAP)进行的类似研究正在进行中。这些假定的基因为理解高血压提供了新的靶点，但绝大多数HTN易感性的遗传变异仍然难以捉摸。我们提出了一项全面的研究，以探索罕见和常见的基因组变异在欧洲(EA)和非洲(AA)美国血统个体中对SBP、DBP和HTN的作用，使用现代基因组方法，包括外显子组测序和包括基因-基因和基因-环境相互作用的新统计方法。这项研究包括来自ARIC(社区动脉粥样硬化风险)、FBPP(家庭血压计划)、WHI(妇女健康倡议)和CARDIA(青年冠状动脉风险发展)队列的DNA样本、基因型和表型，并使用CHARE(心脏和老龄化基因组流行病学研究队列)、CARE(候选基因关联资源)、ICBP(国际血压联盟)和RFGEH(基因、环境和健康研究计划)联盟/研究的数据和荟萃分析复制研究结果。我们将探索：(1)使用所有已知的多态标记的第三代BP和HTN GWA；(2)使用所有可识别的稀有变种的第一代BP和HTN EWAS(外显子组范围的关联研究)；以及(3)BP和HTN变异性中的基因-基因和基因-环境相互作用。好了！ 公共卫生相关性：对不同血压特征的全基因组关联研究，即原发性高血压的中间表型及其对靶器官损害的后果，最近成功地识别了29个基因座，但在对70,000个欧洲血统样本进行荟萃分析后，仅解释了2.5%的表型变异。在这项建议中，我们通过研究人类基因组中的所有多态性，评估稀有变异在外显子组中的作用以及基因与环境相互作用的作用，进行计算和分子遗传学实验，以增加基因发现。我们的目标是提高对血压调节和高血压风险个体差异的分子遗传学的了解。

DESCRIPTION (provided by applicant): Despite decades of research on blood pressure (BP) physiology, our understanding of the biological basis of clinical hypertension (HTN) is still wanting. Recent, genome-wide association studies (GWAS) in ~70,000 individuals of European ancestry have been successful in identifying common variants at 29 loci that explain 2.5% of the inter-individual variation in systolic- (SBP) and diastolic- (DBP) blood pressure, with concomitant effects on HTN. Similar studies are ongoing using pulse (PP) and mean arterial (MAP) pressure. These putative genes provide new targets for understanding essential hypertension but the vast majority of the genetic variation in HTN susceptibility remains elusive. We propose a comprehensive study to explore the role of rare and common genomic variation on SBP, DBP and HTN in individuals of European (EA) and African (AA) American ancestry using contemporary genomic methods including exome sequencing and novel statistical methods that include gene-gene and gene-environment interactions. This study includes DNA samples, genotypes and phenotypes from the ARIC (Atherosclerosis Risk in Communities), FBPP (Family Blood Pressure Program), WHI (Women's Health Initiative) and CARDIA (Coronary Artery Risk Development In Young Adults) cohorts, with replication of findings using data and meta-analysis from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), CARe (Candidate-gene Association Resource), ICBP (International Consortium of Blood Pressure GWAS) and RFGEH (Research Program in Genes, Environment and Health) consortia/studies. We will explore: (1) A third generation BP and HTN GWAS using all known polymorphic markers; (2) a first generation BP and HTN EWAS (exome-wide association study) using all identifiable rare variants; and, (3) gene-gene and gene-environment interactions in BP and HTN variability. ! PUBLIC HEALTH RELEVANCE: Genome-wide association studies for the different blood pressure traits, that are intermediate phenotypes for essential hypertension and its consequences for target organ damage, have recently been successful with 29 loci identified but explaining only 2.5% of the phenotypic variance upon meta-analyses of 70,000 samples of European ancestry. In this proposal, we conduct computational and molecular genetic experiments to increase gene discovery by studying all polymorphisms in the human genome, assessing the role of rare variants in the exome and the role of gene- environment interactions. Our aims are to improve the molecular genetic understanding of blood pressure regulation and inter-individual variation on hypertension risk.