Shared additive- and variance-associated genetic architecture of cardiac structure and function

Abstract

Cardiac remodeling underlies cardiomyopathy and heart failure, yet how common genetic effects are organized across the four chambers, and whether they influence phenotypic variability beyond additive genetic effects, remains unclear. We analyzed 22 cardiac magnetic resonance phenotypes in up to 77,271 UK Biobank participants. Additive mapping identified 748 locus-trait associations across 239 regions. Multivariate fine-mapping revealed that 96% of signals showed effects across multiple cardiac chambers, while resolving independent signals with distinct anatomical profiles, including predominantly atrial and ventricular signals at RBM20. Fine-mapped signal sharing formed three robust communities corresponding broadly to atrial function, chamber remodeling and ventricular systolic function. Variance mapping identified 19 associations, 13 without a nearby additive signal. Individual variance loci and polygenic effects generalized to clinical echocardiographic phenotypes and outcomes in the Penn Medicine Biobank. These findings reveal cardiac common-variant architecture as broadly shared yet locally heterogeneous and identify phenotypic variability as a partly distinct genetic dimension.