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. 2026 Feb 1;11(2):147-155.
doi: 10.1001/jamacardio.2025.4739.

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

Sarah A Abramowitz  1   2 , Lily Hoffman-Andrews  3 , David Zhang  4   5 , Renae Judy  1 , Thomas P Cappola  4   6 , Sharlene M Day  3   4   6 , Nosheen Reza  3   6 , Anjali T Owens  3   6 , Scott M Damrauer  1   4   5   7 , Michael G Levin  4   6   7 ; Penn Medicine BioBank
Collaborators, Affiliations

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

Sarah A Abramowitz et al. JAMA Cardiol. .

Abstract

Importance: 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.

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

Design, setting, and participants: 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.

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

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

Results: 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.

Conclusions and relevance: 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Abramowitz reported grants from Sarnoff Cardiovascular Research Foundation during the conduct of the study. Dr Day reported grants from Lexicon Pharmaceuticals and Bristol Myers Squibb and personal fees from Lexicon Pharmaceuticals, Cytokinetics, and Solid Biosciences outside the submitted work. Dr Reza reported grants from the National Heart, Lung, and Blood Institute during the conduct of the study as well as personal fees from Zoll, Roche Diagnostics, AstraZeneca, Novo Nordisk, American Regent, Cytokinetics, Bristol Myers Squibb, and Idorsia and grants from Bristol Myers Squibb outside the submitted work. Dr Owens reported consulting for Alexion, Avidity, Bayer, Bristol Myers Squibb, Cytokinetics, Corvista, Edgewise, Lexeo, Imbria, Stealth, and Tenaya outside the submitted work. Dr Damrauer reported personal fees from Tourmaline Bio, nonfinancial support from Amgen and Novo Nordisk, and grants from the National Heart, Lung, and Blood Institute and the US Department of Veterans Affairs outside the submitted work. Dr Levin reported grants from the US Department of Veterans Affairs and the Doris Duke Foundation during the conduct of the study as well as grants from MyOme and personal fees from BridgeBio outside the submitted work. No other disclosures were reported.

Update of

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