Evaluation of polygenic scores for hypertrophic cardiomyopathy in the general population and across clinical settings

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality, with pathogenic variants found in about a third of cases. Large-scale genome-wide association studies (GWAS) demonstrate that common genetic variation contributes to HCM risk. Here we derive polygenic scores (PGS) from HCM GWAS and genetically correlated traits and test their performance in the UK Biobank, 100,000 Genomes Project, and clinical cohorts. We show that higher PGS significantly increases the risk of HCM in the general population, particularly among pathogenic variant carriers, where HCM penetrance differs 10-fold between those in the highest and lowest PGS quintiles. Among relatives of HCM probands, PGS stratifies risks of developing HCM and adverse outcomes. Finally, among HCM cases, PGS strongly predicts the risk of adverse outcomes and death. These findings support the broad utility of PGS across clinical settings, enabling tailored screening and surveillance and stratification of risk of adverse outcomes.

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Publication Details

Journal
Nature Genetics
Published
2025-02-18
DOI
https://doi.org/10.1038/s41588-025-02094-5
Citations
32
Primary Topic
Cardiomyopathy and Myosin Studies
Type
article
Field-Weighted Citation Impact
44.42

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article

Evaluation of polygenic scores for hypertrophic cardiomyopathy in the general population and across clinical settings

Hak Chiaw Tang, Judith M.A. Verhagen, Connie R. Bezzina, Michelle Michels et al.
32 citations
Nature Genetics
Cardiomyopathy and Myosin Studies
44.42
article

Evaluation of polygenic scores for hypertrophic cardiomyopathy in the general population and across clinical settings

Hak Chiaw Tang, Judith M.A. Verhagen, Connie R. Bezzina, Michelle Michels, James S. Ware, Antonios Pantazis, Rafik Tadros, Paul J.R. Barton, Chee Jian Pua, Catherine Francis, Sean L. Zheng, Pantazis Theotokis, Hugh Watkins, Rachel Buchan, Brian P. Halliday, Elizabeth Ormondroyd, Andrew R. Harper, Ahmad S. Amin, Calvin Chin, Roddy Walsh, Xiao Yun Xu, Anuj Goel, Wenjia Bai, Yigal M. Pinto, Sanjay Prasad, Declan P. O’Regan, Lara Curran, Paul M. Matthews, Marjon A. van Slegtenhorst, Stuart A. Cook, Antonio de Marvao, Kathryn A. McGurk, Sean J. Jurgens, R Thomas Lumbers, Paloma Jordà, John Baksi, Chris Grace, Arthur A.M. Wilde
article en
32 citations

Abstract

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality, with pathogenic variants found in about a third of cases. Large-scale genome-wide association studies (GWAS) demonstrate that common genetic variation contributes to HCM risk. Here we derive polygenic scores (PGS) from HCM GWAS and genetically correlated traits and test their performance in the UK Biobank, 100,000 Genomes Project, and clinical cohorts. We show that higher PGS significantly increases the risk of HCM in the general population, particularly among pathogenic variant carriers, where HCM penetrance differs 10-fold between those in the highest and lowest PGS quintiles. Among relatives of HCM probands, PGS stratifies risks of developing HCM and adverse outcomes. Finally, among HCM cases, PGS strongly predicts the risk of adverse outcomes and death. These findings support the broad utility of PGS across clinical settings, enabling tailored screening and surveillance and stratification of risk of adverse outcomes.

Nature GeneticsVol. 57(3)
Broad Institute (US), University of London (GB), Centre for Human Genetics (GB), Imperial College Healthcare NHS Trust (GB), National University of Singapore (SG), King's College London (GB), Guy's and St Thomas' NHS Foundation Trust (GB), Royal Brompton & Harefield NHS Foundation Trust (GB), Montreal Heart Institute (CA), Erasmus MC (NL), John Radcliffe Hospital (GB), Harefield Hospital (GB), British Heart Foundation (GB), University of Oxford (GB), Lung Institute (US), NIHR Imperial Biomedical Research Centre (GB), Health Data Research UK (GB), National Heart Centre Singapore (SG), Amsterdam University Medical Centers (NL), Institute of Group Analysis (GB), University College London (GB), Imperial College London (GB), Université de Montréal (CA), University of Amsterdam (NL), Medical Research Council (GB)
Wellcome Trust, Maudsley Charity, Gujarat Council on Science and Technology, Cancer Research UK, National Institute for Health and Care Research, British Heart Foundation, Department of Health and Social Care, European Commission, Rosetrees Trust, Fondation Leducq, Fetal Medicine Foundation, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Medical Research Council
Good health and well-being
Openalex Percentile: Top 0%
Cardiomyopathy and Myosin Studies
44.42
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