Key result
Highest multiancestry PRS quintile linked to ~111% greater HCM risk.
Why the study?
Sarcomeric variants explain only one-third of HCM cases, and existing polygenic risk scores derived largely from European-ancestry cohorts have limited generalizability.
Does a multiancestry polygenic risk score improve risk stratification for hypertrophic cardiomyopathy in a multiancestry population?
Observational
Yes
Does a multiancestry polygenic risk score improve risk stratification for hypertrophic cardiomyopathy in a multiancestry population?
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“For most patients with hypertrophic cardiomyopathy, a single mutation doesn't tell the whole story. Common genetic variation, or the thousands of small effects spread across the genome, play a major role. By capturing the common genetic variation with a polygenic risk score built for diverse populations, we can begin to explain risk in the many patients who currently receive no genetic explanation for their disease.”
“Populations that have been underrepresented in genetic research are the most likely to receive inconclusive test results. By building this score from more diverse data, we saw trends toward better prediction in African and Admixed American populations. We also saw something important: Adding diverse data improved prediction even in European-ancestry individuals, because it helps separate true causal signals from statistical noise.”
A multiancestry polygenic risk score significantly improves risk stratification for hypertrophic cardiomyopathy, particularly among carriers of pathogenic sarcomere variants.
Hypertrophic cardiomyopathy (HCM) has traditionally been considered a Mendelian disease driven by pathogenic or likely pathogenic variants in sarcomere-encoding genes (SARC-HCM-P/LP). However, these variants explain only one-third of cases, and variable penetrance suggests additional polygenic contributions. Existing HCM polygenic risk scores (PRSs), largely derived from European-ancestry cohorts, have limited generalizability. Here we develop a multiancestry PRS using summary statistics from the BioBank Japan, Million Veteran Program and a meta-analysis of seven European-ancestry cohorts and evaluate its association with HCM in a USA-based multiancestry population. Individuals with the highest PRS quintile had a 2.11-fold increased risk of HCM in the overall population and nearly 70-fold higher risk among SARC-HCM-P/LP carriers. The PRS improved risk stratification and showed trends toward improved ancestry-specific prediction. Among individuals with HCM, a higher PRS was also associated with adverse cardiovascular outcomes. These findings support the integration of multiancestry PRSs into HCM risk assessment and prognostication.
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Bal et al. (2026) conducted an observational in Hypertrophic cardiomyopathy (HCM). Multiancestry polygenic risk score (PRS) vs. Lower PRS quintiles was evaluated on Hypertrophic cardiomyopathy (HCM) (2.11-fold increased risk). Individuals in the highest multiancestry polygenic risk score quintile had a 2.11-fold increased risk of HCM overall and a nearly 70-fold higher risk among SARC-HCM-P/LP carriers.
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