Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy

Journal article

R. Tadros, Sean L. Zheng, C. Grace, P. Jordà, C. Francis, Dominique M West, S. Jurgens, K. Thomson, Andrew R. Harper, Elizabeth Ormondroyd, Xiao Xu, P. Theotokis, R. Buchan, K. McGurk, F. Mazzarotto, B. Boschi, E. Pelo, Michael Lee, M. Noseda, A. Varnava, A. Vermeer, Roddy Walsh, A. Amin, M. V. van Slegtenhorst, N. Roslin, L. Strug, Erika Salvi, C. Lanzani, A. de Marvao, Daniele Paolo Lorena Nicola Cusi Manunta Citterio Glorioso, D. Cusi, P. Manunta, L. Citterio, Nicola Glorioso, Jason D. Roberts, M. Tremblay‐Gravel, G. Giraldeau, J. Cadrin-Tourigny, P. L’allier, P. Garceau, M. Talajic, S. G. Gagliano Taliun, Y. Pinto, Harry Rakowski, A. Pantazis, Wenjia Bai, J. Baksi, B. Halliday, Sanjay K. Prasad, Paul J. R. Barton, D. O’Regan, Stuart A. Cook, Rudolf A. de Boer, I. Christiaans, M. Michels, Christopher M. Kramer, C. Ho, S. Neubauer, Theodore Lisa Florian Evan Camillo Lauren Colin Elena Willi Abraham Anderson Andre Appelbaum Autore Baldassarr, T. Abraham, Lisa Anderson, F. André, E. Appelbaum, C. Autore, Lauren Baldassarre, Colin Berry, E. Biagini, William Bradlow, Chiara Bucciarelli-Ducci, A. Chiribiri, L. Choudhury, Andrew Crean, Dana Dawson, M. Desai, P. Desvigne-Nickens, J. DiMarco, E. Elstein, Andrew S. Flett, Matthias Friedrich, Eli V. Gelfand, Nancy Geller, T. Germans, J. Geske, A. Hays, S. Heitner, A. Helms, Daniel L. Jacoby, Dong-Yun Kim, Bette Kim, Han Kim, P. Kolm, R. Kwong, Eric Larose, C. Madias, M. Mahmod, H. Mahrholdt, M. Maron, A. Masri, G. McCann, S. Mohiddin, F. Mongeon, S. Nagueh, D. Newby, A. Nightingale, Anjali Owens, S. Plein, B. Raman, O. Rimoldi, Michael Salerno, Jeanette Schulz-Menger, Sanjay Sharma, M. Sherrid, A. V. van Rossum, Jonathan W. Weinsaft, W. Weintraub, J. White, Eric Williamson, Anna Woo, P. Matthews, A. Wilde, J. Tardif, I. Olivotto, Arnon Adler, A. Goel, James S. Ware, C. Bezzina, Hugh Watkins
Nature Genetics, 2025

Semantic Scholar DOI PubMedCentral PubMed

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APA Click to copy
Tadros, R., Zheng, S. L., Grace, C., Jordà, P., Francis, C., West, D. M., … Watkins, H. (2025). Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy. Nature Genetics.

Chicago/Turabian Click to copy
Tadros, R., Sean L. Zheng, C. Grace, P. Jordà, C. Francis, Dominique M West, S. Jurgens, et al. “Large-Scale Genome-Wide Association Analyses Identify Novel Genetic Loci and Mechanisms in Hypertrophic Cardiomyopathy.” Nature Genetics (2025).

MLA Click to copy
Tadros, R., et al. “Large-Scale Genome-Wide Association Analyses Identify Novel Genetic Loci and Mechanisms in Hypertrophic Cardiomyopathy.” Nature Genetics, 2025.

BibTeX Click to copy

@article{r2025a,
  title = {Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy},
  year = {2025},
  journal = {Nature Genetics},
  author = {Tadros, R. and Zheng, Sean L. and Grace, C. and Jordà, P. and Francis, C. and West, Dominique M and Jurgens, S. and Thomson, K. and Harper, Andrew R. and Ormondroyd, Elizabeth and Xu, Xiao and Theotokis, P. and Buchan, R. and McGurk, K. and Mazzarotto, F. and Boschi, B. and Pelo, E. and Lee, Michael and Noseda, M. and Varnava, A. and Vermeer, A. and Walsh, Roddy and Amin, A. and van Slegtenhorst, M. V. and Roslin, N. and Strug, L. and Salvi, Erika and Lanzani, C. and de Marvao, A. and Glorioso, Daniele Paolo Lorena Nicola Cusi Manunta Citterio and Cusi, D. and Manunta, P. and Citterio, L. and Glorioso, Nicola and Roberts, Jason D. and Tremblay‐Gravel, M. and Giraldeau, G. and Cadrin-Tourigny, J. and L’allier, P. and Garceau, P. and Talajic, M. and Taliun, S. G. Gagliano and Pinto, Y. and Rakowski, Harry and Pantazis, A. and Bai, Wenjia and Baksi, J. and Halliday, B. and Prasad, Sanjay K. and Barton, Paul J. R. and O’Regan, D. and Cook, Stuart A. and de Boer, Rudolf A. and Christiaans, I. and Michels, M. and Kramer, Christopher M. and Ho, C. and Neubauer, S. and Baldassarr, Theodore Lisa Florian Evan Camillo Lauren Colin Elena Willi Abraham Anderson Andre Appelbaum Autore and Abraham, T. and Anderson, Lisa and André, F. and Appelbaum, E. and Autore, C. and Baldassarre, Lauren and Berry, Colin and Biagini, E. and Bradlow, William and Bucciarelli-Ducci, Chiara and Chiribiri, A. and Choudhury, L. and Crean, Andrew and Dawson, Dana and Desai, M. and Desvigne-Nickens, P. and DiMarco, J. and Elstein, E. and Flett, Andrew S. and Friedrich, Matthias and Gelfand, Eli V. and Geller, Nancy and Germans, T. and Geske, J. and Hays, A. and Heitner, S. and Helms, A. and Jacoby, Daniel L. and Kim, Dong-Yun and Kim, Bette and Kim, Han and Kolm, P. and Kwong, R. and Larose, Eric and Madias, C. and Mahmod, M. and Mahrholdt, H. and Maron, M. and Masri, A. and McCann, G. and Mohiddin, S. and Mongeon, F. and Nagueh, S. and Newby, D. and Nightingale, A. and Owens, Anjali and Plein, S. and Raman, B. and Rimoldi, O. and Salerno, Michael and Schulz-Menger, Jeanette and Sharma, Sanjay and Sherrid, M. and van Rossum, A. V. and Weinsaft, Jonathan W. and Weintraub, W. and White, J. and Williamson, Eric and Woo, Anna and Matthews, P. and Wilde, A. and Tardif, J. and Olivotto, I. and Adler, Arnon and Goel, A. and Ware, James S. and Bezzina, C. and Watkins, Hugh}
}

Abstract

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Here, we report results from a large genome-wide association study and multitrait analysis including 5,900 HCM cases, 68,359 controls and 36,083 UK Biobank participants with cardiac magnetic resonance imaging. We identified 70 loci (50 novel) associated with HCM and 62 loci (20 novel) associated with relevant left ventricular traits. Among the prioritized genes in the HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants confer a roughly tenfold increased risk of HCM. Mendelian randomization analyses support a causal role of increased left ventricular contractility in both obstructive and nonobstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, these findings increase our understanding of the genetic basis of HCM, with potential implications for disease management. Genome-wide and multitrait analyses identify novel loci associated with hypertrophic cardiomyopathy and relevant left ventricular traits. Gene-level burden analyses show that rare truncating SVIL variants are associated with high risk of hypertrophic cardiomyopathy.