Polygenic Background and Penetrance of Pathogenic Variants in Hypertrophic and Dilated Cardiomyopathies

Polygenic background modifies variant penetrance in hypertrophic (HCM) and dilated (DCM) cardiomyopathies, diseases with opposing morphologic characteristics and inversely related genetic pathways. Whether polygenic susceptibility for one disease protects against monogenic risk for the other remains uncertain.

To characterize if polygenic background bidirectionally modifies pathogenicity of established rare variants associated with HCM and DCM.

This cross-sectional study was conducted using data from the Penn Medicine BioBank (PMBB). Volunteers enrolled in PMBB between November 1994 and July 2022 with available electronic health record and genotyping data through September 2024 were included. Analysis was performed in June 2025.

Normalized polygenic scores (PGSs) for HCM and DCM as well as carrier status of pathogenic variants in established HCM or DCM genes.

HCM and DCM defined using electronic health record diagnosis and procedure codes, as well as echocardiogram measurements obtained from medical records.

This study included 49 434 PMBB participants (median (IQR) age, 57 [42-67] years; 24 886 male [50.3%]). An increased HCM PGS was associated with a 1.1% increase in left ventricular ejection fraction (LVEF; 95% 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-SD 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 (estimate, -1.3 × 10⁻3 mm; 95% CI, -0.04 to 0.03; P = .94). A 1-SD increase in HCM PGS was associated with an increased risk of HCM (odds ratio [OR], 1.8; 95% CI, 1.6-2.0; P = 9.6 × 10-25) and decreased risk of DCM (OR, 0.69; 95% CI, 0.64-0.74; P = 4.3 × 10-22). A 1-SD increase in DCM PGS was associated with an increased risk of DCM (OR, 1.6; 95% CI, 1.5-1.7; P = 1.7 × 10-40) and decreased risk of HCM (OR, 0.69; 95% CI, 0.63-0.76; P = 3.0 × 10-13). Monogenic and polygenic risk terms had significant independent effects when combined in models of disease status and echocardiographic measurements; the inclusion of either an HCM or DCM PGS improved the discrimination (area under the receiving operating characteristic curve) of models of HCM (0.043; 95% credible interval, 0.034-0.053) and DCM (0.045; 95% credible interval, 0.039-0.051) beyond models including age, sex, and monogenic variant status.

The findings in this study indicate that HCM and DCM risk were modified by polygenic background, which exists on an overlapping but opposing spectrum. Consideration of polygenic background may offer clinical value through improving understanding and prediction of these inherited cardiomyopathies.