Can common genetic background modify the expression of inherited cardiomyopathies with opposing phenotypes? In JAMA Cardiology, a cross-sectional analysis evaluated whether polygenic susceptibility modifies cardiac structure, function, and disease risk in hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM).

The study included 49,434 participants with available electronic health record and genotyping data. Median age was 57 years (interquartile range [IQR], 42-67 years), and 24,886 participants (50.3%) were male. Normalized polygenic scores (PGSs) for HCM and DCM and carrier status of pathogenic variants in established cardiomyopathy genes were assessed. A higher HCM PGS was associated with a 1.1% increase in left ventricular ejection fraction (LVEF; 95% confidence interval [CI], 0.9 to 1.3; P = 7.3 × 10⁻³¹), a 0.79-mm decrease in left ventricular internal diameter at end-diastole (LVIDd; 95% CI, −0.92 to −0.67; P = 2.3 × 10⁻³⁶), and a 0.18-mm increase in interventricular septal (IVS) thickness (95% CI, 0.14 to 0.22; P = 9.3 × 10⁻¹⁹).

A 1-standard deviation increase in DCM PGS was associated with a 2.0% decrease in LVEF (95% CI, −2.2 to −1.8; P = 3.3 × 10⁻⁸³) and a 1.0-mm increase in LVIDd (95% CI, 0.93 to 1.1; P = 3.2 × 10⁻⁷⁸) and was not significantly associated with IVS thickness (estimate, −1.3 × 10⁻³ mm; 95% CI, −0.04 to 0.03; P = .94). Higher HCM PGS was associated with increased odds of HCM (odds ratio [OR], 1.8; 95% CI, 1.6-2.0; P = 9.6 × 10⁻²⁵) and reduced odds of DCM (OR, 0.69; 95% CI, 0.64-0.74; P = 4.3 × 10⁻²²), whereas higher DCM PGS showed the opposite pattern. Inclusion of either HCM or DCM PGS improved discrimination of disease models beyond age, sex, and monogenic variant status.

These findings show that HCM and DCM risk are modified by an opposing polygenic background spectrum.