Pankaj Arora, M.D., Garima Arora, M.D. and Harshvir Bal, M.D.Researchers from the University of Alabama at Birmingham Marnix E. Heersink School of Medicine and collaborating institutions have developed a multi-ancestry polygenic risk score that improves how clinicians identify people at risk for hypertrophic cardiomyopathy, the most common inherited heart muscle disease. The study, published in Nature Cardiovascular Research, shows that combining the effects of many common genetic variants into a single score can refine risk assessment across diverse populations, and even among patients whose current genetic tests return uncertain results.
HCM affects roughly one in 500 people and is a leading cause of sudden cardiac death in young people, as well as a cause of heart failure, arrhythmias and stroke. For decades, HCM has been viewed largely as a “Mendelian” disease driven by rare pathogenic mutations in genes that build the heart muscle’s contractile machinery, such as MYBPC3 and MYH7. But those mutations are found in only about a third of patients, and even people who carry them do not always develop disease, a puzzle that has limited the usefulness of genetic testing.
The genetic causes of HCM can be understood by determining whether a patient’s disease follows a Mendelian or polygenic pattern. The impact of Mendelian diseases is often caused by a single inherited genetic trait or mutation, which can vary based on the individual. In contrast, diseases such as HCM are also considered polygenic, meaning many and various types of genetic differences can collectively influence an individual’s risk, rather than a single gene alone.
“For most patients with hypertrophic cardiomyopathy, a single mutation doesn’t tell the whole story,” said Pankaj Arora, M.D., senior author and director of the UAB Cardiogenomics Clinic. “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 whose standard genetic tests come back negative or uncertain.”
To build the score, the team combined genetic data from three large programs, the Biobank Japan, the Department of Veterans Affairs Million Veteran Program and European-ancestry cohorts, deliberately incorporating a larger share of non-European data than prior HCM scores. They tested the score in more than 250,000 participants from the All of Us Research Program , a diverse cohort from the United States that included individuals of European, African, Admixed American and Asian ancestry, and validated it in the UK Biobank.
“These findings move us toward a more complete, more inclusive picture of who is at risk for hypertrophic cardiomyopathy,” Arora said. “Combined with the falling cost of genetic sequencing and the arrival of disease-specific therapies, integrating polygenic risk into clinical assessment could help us find and protect the right patients earlier.”
In the overall population, people in the highest genetic risk group had a 2.11-fold higher risk of developing HCM compared with those in the lowest. The score’s power was greatest when combined with rare-variant status: Carriers of a pathogenic sarcomere mutation who also had a high polygenic score had a nearly 70-fold increased risk of HCM, and more than a 3.5-fold higher risk than mutation carriers with a low score. This shows that a person’s broader genetic background strongly influences whether a known high-risk mutation leads to disease.
The score addressed one of the most frustrating problems in cardiac genetics: variants of unknown significance. Patients who carry a sarcomere variant of unknown significance are often left without clear guidance because the variant’s meaning is uncertain. In this study, such carriers with a high polygenic score had a more than fourfold higher risk of developing HCM, while those with a low score showed no significant increase, suggesting the score could help reclassify these ambiguous results into actionable risk information.
“Populations that have been underrepresented in genetic research are the most likely to receive inconclusive test results,” said Harshvir S. Bal, M.D., first author of the study. “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.”
Key Takeaways:
- A multi-ancestry polygenic risk score improved HCM risk prediction in a diverse U.S. population of more than 258,000 people.
- People in the highest genetic risk group had a 2.11-fold higher risk of HCM overall; sarcomere mutation carriers with a high score had a nearly 70-fold higher risk.
- The score refined risk among carriers of variants of unknown significance, a group current tests cannot classify.
- Higher scores were linked to worse outcomes, including heart failure, in people with HCM.
- Incorporating diverse genetic data improved prediction across all ancestry groups, including European.
Beyond predicting who develops HCM, the score also tracked outcomes. Among patients who already had HCM, sarcomere mutation carriers with a high polygenic score faced a nearly twofold higher risk of heart failure. The researchers observed that a higher HCM genetic score was associated with a modestly lower risk of dilated cardiomyopathy, consistent with growing evidence that these two heart muscle diseases sit at opposite ends of a shared genetic spectrum.
“Genetic risk scores are moving into the clinic, and if they are built only from European data, they risk widening health disparities,” said co-author Garima Arora, M.D., co-director of the UAB Cardiogenomics Clinic. “This work shows a path toward tools that work more equitably across populations, though we clearly need larger and more diverse genetic studies to close the remaining gaps.”
The authors called for continued expansion of genetic research in diverse populations, and this study represented a step toward truly personalized and equitable cardiovascular care. To learn more about cardiogenomics research and cardiovascular care, visit the UAB Cardiovascular Institute.