Genome-wide Association Study of Cardiac Structure and Function

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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.