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Heart failure is a major cause for premature death. Given heterogeneity ofthe heart failure syndrome, identifying genetic determinants of cardiacfunction and structure may provide greater insights into heart failure. Despiteprogress in understanding the genetic basis of heart failure through genomewide association studies, heritability of heart failure is not well understood.Gaining further insights into mechanisms that contribute to heart failurerequires systematic approaches that go beyond single trait analysis. Weintegrated Bayesian multi-trait approach and Bayesian networks for the analysisof 10 correlated traits of cardiac structure and function measured for 3387individuals with whole exome sequence data. While using single-trait basedapproaches did not find any significant genetic variant, applying theintegrative Bayesian multi-trait approach, we identified 3 novel variantslocated in genes, RGS3, CHD3, and MRPL38 with significant impact on the cardiactraits such as left ventricular volume index, parasternal long axisinterventricular septum thickness, and mean left ventricular wall thickness.Among these, the rare variant NC_9.11:g.116346115C>A (rs144636307) in RGS3showed pleiotropic effect on left ventricular mass index, left ventricularvolume index and Maximum left atrial anterior-posterior diameter while RGS3 caninhibit TGF-beta signaling associated with left ventricle dilation and systolicdysfunction.

A Multi-Trait Approach Identified Genetic Variants Including a Rare Mutation in RGS3 with Impact on Abnormalities of Cardiac Structure/Function