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，与家族易感性有关。左心室(LV)重构早于CHF数月至数年，其特征是左室大小、室壁厚度、几何形状以及收缩和舒张期功能的变化。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的评估、定量的性质、实质性的遗传性、与CHF的既定关系以及更接近遗传影响(相对于CHF的更远端的表型)。在几个基于社区的队列上进行密集基因组扫描的可用性提供了一个难得的机会，可以使用全基因组关联研究(Gwas)来研究ECHO特征的遗传基础，从而为社区CHF的发病机制提供深入的见解。我们假设，在社区中，常见的遗传变异导致了左心室质量、内径和收缩功能、室壁厚度、左心房(LA)和主动脉根部大小的个体间差异。为了发现影响回声特征的共同变异，我们成立了一个联盟(Echogen)，将在6个队列中分析以前资助的GWA(阶段1)，并在3个外部队列中复制最强的发现(阶段2)。我们的具体目标是：1.通过对6项队列研究(鹿特丹弗雷明翰心血管健康研究、预防、SHIP和MONICA-KORA；17,600名参与者)中的回声特征(左心室质量、大小、壁厚、收缩功能障碍；左房和主动脉根部大小)进行荟萃分析，使用GWAS来识别影响回声特征的常见变量。目的2.通过复制在另外3个队列(Mayo Clinic、PIVUS、CALA；4,770名参与者)中发现的前175个变异(每个性状约30个×6个ECHO性状)，并执行结合阶段1和2的Meta分析来复制GWAS的发现。目的3.检查影响ECHO性状的基因-环境和上位性(基因-基因)交互作用；环境因素包括年龄、性别、高血压和肥胖。拟议的利用现有队列的多机构、多国合作(Echogen)将揭示基因变异对ECHO特征的贡献，并为CHF的风险分层和未来治疗确定新的靶点。公共卫生相关性：人们患心力衰竭(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发挥着关键作用。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项大型国际研究中超过22,000名参与者的密集基因扫描的结果联系起来。这些分析可能会确定心脏改变的遗传风险因素，这些改变反过来会使个人容易发生心力衰竭。

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.