Polygenic Risk Modifies Penetrance and Outcomes in Hypertrophic Cardiomyopathy: Insights from a US-Based Multi-Ancestry Cohort
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Hypertrophic cardiomyopathy (HCM) has traditionally been considered a Mendelian disease driven by pathogenic/likely pathogenic variants in sarcomere encoding genes (SARC-HCM-P/LP). However, these variants explain only one-third of the HCM cases, and variable penetrance suggests polygenic contributions. Existing HCM polygenic risk scores (PRSs) have been derived primarily from European ancestry cohorts, limiting their generalizability. In this study, a multi-ancestry PRS for HCM was developed using summary statistics from the Biobank Japan, Million Veterans Program, and a meta-analysis of seven European-ancestry cohorts and evaluated to assess association with HCM risk in a multiancestry US-based population. Higher PRS was associated with increased HCM risk, including among SARC-HCM-P/LP carriers, improving risk-stratification, despite variable penetrance. Incorporation of larger non-European datasets enhanced ancestry-stratified risk prediction. Among individuals with HCM, the PRS also improved prediction of adverse cardiovascular outcomes. These findings support the integration of multi-ancestry PRS into clinical care to refine HCM risk assessment and prognostication.
