Genome-wide Association Study of Cardiac Structure and Function

描述（由申请人提供）：充血性心力衰竭（CHF）是美国发病率和死亡率的主要原因，与家族易感性相关。左室（LV）重构早于CHF数月至数年，其特征是左室尺寸、壁厚、几何形状以及收缩和舒张功能的改变。因此，超声心动图（echo）特征可以作为遗传分析的内表型，因为它们具有可重复性评估、定量性质、大量遗传性、与CHF建立的关系以及更接近遗传影响（相对于CHF的远端表型）。在几个社区队列中密集基因组扫描的可用性为使用全基因组关联研究（GWAS）来调查回声特征的遗传基础提供了一个绝佳的机会，从而为社区中CHF的发病机制提供了见解。我们假设常见的遗传变异导致了社区中左室质量、尺寸和收缩功能、壁厚、左房（LA）和主动脉根大小的个体间差异。为了发现影响回声特征的共同变异，我们建立了一个联盟（EchoGen），该联盟将分析先前资助的6个队列（第一阶段）的GWAS，并在3个外部队列（第二阶段）中重复最强的发现。我们的具体目标是：目标1。通过对6项队列研究（Framingham、鹿特丹、心血管健康研究、prevention -it、SHIP和MONICA-KORA； 17,600名参与者）中回声特征（左室质量、尺寸、壁厚、收缩功能障碍、左心房和主动脉根大小）的GWAS进行meta分析，利用GWAS识别影响回声特征的常见变异。目标2。通过复制另外3个队列（Mayo clinic， PIVUS， CARLA; 4,770名参与者）中发现的175个变异（每个性状约30个× 6个回声性状）来复制GWAS的发现；并结合第一阶段和第二阶段进行meta分析。目标3。探讨基因-环境和上位性（基因-基因）相互作用对回声性状的影响；环境因素包括年龄、性别、高血压和肥胖。拟议的多机构、跨国合作（EchoGen）利用现有的队列（具有GWAS）将揭示遗传变异对回声特征的贡献，并确定风险分层和未来治疗CHF的新靶点。公共卫生相关性：人与人之间患心力衰竭（心脏泵血不足）的风险有相当大的差异，遗传影响与环境因素一起在决定风险方面起着关键作用。在这个项目中，研究人员建议将心脏测量（通过超声波获得）与9项大型国际研究中22,000多名参与者的密集基因扫描结果联系起来。这些分析可能会确定心脏改变的遗传风险因素，从而使个体易患心力衰竭。

DESCRIPTION (provided by applicant): Congestive heart failure (CHF) is a major cause of morbidity and mortality in the United States that is associated with a familial predisposition. Left ventricular (LV) remodeling antedates CHF by months to years and is characterized by changes in LV dimensions, wall thickness, geometry and systolic and diastolic function. Thus, echocardiographic (echo) traits can serve as endophenotypes for genetic analyses, given their reproducible assessment, quantitative nature, substantial heritability, established relations to CHF, and greater proximity to genetic influences (relative to the more distal phenotype of CHF). The availability of dense genome scans on several community-based cohorts offers a remarkable opportunity to use genome- wide association studies (GWAS) to investigate the genetic underpinnings of echo traits, thereby providing insights into pathogenesis of CHF in the community. We hypothesize that common genetic variants contribute to interindividual variation in LV mass, dimensions and systolic function, wall thickness, left atrial (LA) and aortic root size in the community. To discover common variation influencing echo traits, we have established a consortium (EchoGen) that will analyze previously-funded GWAS in 6 cohorts (stage 1), and replicate the strongest findings in 3 external cohorts (stage 2). Our specific aims are: Aim 1. To use GWAS to identify common variants influencing echo traits by performing a meta-analysis of GWAS for echo traits (LV mass, dimensions, wall thickness, systolic dysfunction; left atrial and aortic root size) in 6 cohort studies (Framingham, Rotterdam, Cardiovascular Health Study, PREVENT-it, SHIP, and MONICA-KORA; 17,600 participants). Aim 2. To replicate GWAS findings by replicating the top 175 variants (~30 per trait x 6 echo traits) identified in 3 additional cohorts (Mayo clinic, PIVUS, CARLA; 4,770 participants); and performing a meta- analysis that combines stages 1 and 2. Aim 3. To examine gene-environment and epistasis (gene-gene) interactions influencing echo traits; the environmental factors include age, sex, hypertension, and obesity. The proposed multi-institutional, multinational collaboration (EchoGen) leveraging existing cohorts (with GWAS) will uncover the contribution of genetic variation to echo traits, and identify novel targets for risk stratification and future therapy of CHF. PUBLIC HEALTH RELEVANCE: There is considerable variation in the risk of suffering heart failure (inadequate pumping of the heart) among people, and genetic influences play a key role together with environmental factors in determining risk. In this project, investigators propose to relate cardiac measurements (obtained via ultrasound) to findings from dense gene scans in over 22,000 participants in 9 large international studies. These analyses will likely identify genetic risk factors for cardiac alterations that in turn predispose individuals to heart failure.