A multiancestry polygenic risk score improves risk stratification in hypertrophic cardiomyopathy, with individuals in the highest PRS quintile having a 2.11-fold increased risk of HCM overall and nearly 70-fold higher risk among sarcomere variant carriers.
Individuals in the highest PRS quintile had a 2.11-fold increased risk of HCM compared to those in the lowest quintile in the overall population.
Among carriers of pathogenic or likely pathogenic sarcomere variants (SARC-HCM-P/LP), individuals in the highest PRS quintile had nearly 70-fold higher risk of HCM.
Existing HCM polygenic risk scores derived largely from European-ancestry cohorts have limited generalizability, motivating development of a multiancestry PRS.
The multiancestry PRS improved risk stratification and showed trends toward improved ancestry-specific prediction of HCM.
Among individuals already diagnosed with HCM, a higher PRS was associated with adverse cardiovascular outcomes.
Hypertrophic cardiomyopathy (HCM) is a heart muscle disease that has long been thought to be caused primarily by mutations in a single gene. However, only about one-third of HCM patients carry these known mutations, and even among those who do, not everyone develops the disease equally severely. This research suggests that a person's overall genetic background — captured by a 'polygenic risk score' (PRS) that summarizes thousands of small genetic variants — plays an important additional role in determining who gets HCM and how severe it becomes. The researchers built a new PRS by combining genetic data from diverse populations in Japan, the United States (including military veterans), and European cohorts, making it more applicable to people of different ancestries than previous scores. This research suggests that people with the highest polygenic risk scores were about twice as likely to develop HCM compared to those with the lowest scores in the general population. Strikingly, among people who already carried a known disease-causing mutation in a sarcomere gene, those with the highest PRS were nearly 70 times more likely to develop HCM than those with the lowest PRS — helping to explain why some mutation carriers develop disease while others do not. Additionally, among people already diagnosed with HCM, a higher PRS was linked to worse cardiovascular outcomes, suggesting the score can help predict disease course, not just who gets it. This research suggests that incorporating polygenic risk scores into clinical evaluation of HCM could improve doctors' ability to identify who is most at risk — especially among people who carry a known genetic mutation — and to anticipate who might have a more serious disease course. The multiancestry design is notable because most previous genetic risk tools were built primarily from people of European descent, limiting their usefulness for patients of other backgrounds. Broader validation across diverse populations will be important before these tools can be widely adopted in clinical care.
Bal H, Pampana A, Nayak A, Gaonkar M, Patel S, Yerabolu K, et al.. (2026). A multiancestry polygenic risk score improves stratification in patients with hypertrophic cardiomyopathy.. Nature cardiovascular research. https://doi.org/10.1038/s44161-026-00866-8