  Heart failure is a major cause for premature death. Given heterogeneity of
the heart failure syndrome, identifying genetic determinants of cardiac
function and structure may provide greater insights into heart failure. Despite
progress in understanding the genetic basis of heart failure through genome
wide association studies, heritability of heart failure is not well understood.
Gaining further insights into mechanisms that contribute to heart failure
requires systematic approaches that go beyond single trait analysis. We
integrated Bayesian multi-trait approach and Bayesian networks for the analysis
of 10 correlated traits of cardiac structure and function measured for 3387
individuals with whole exome sequence data. While using single-trait based
approaches did not find any significant genetic variant, applying the
integrative Bayesian multi-trait approach, we identified 3 novel variants
located in genes, RGS3, CHD3, and MRPL38 with significant impact on the cardiac
traits such as left ventricular volume index, parasternal long axis
interventricular septum thickness, and mean left ventricular wall thickness.
Among these, the rare variant NC_000009.11:g.116346115C>A (rs144636307) in RGS3
showed pleiotropic effect on left ventricular mass index, left ventricular
volume index and Maximum left atrial anterior-posterior diameter while RGS3 can
inhibit TGF-beta signaling associated with left ventricle dilation and systolic
dysfunction.
