| Title: | Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy |
| Journal: | Nature Genetics |
| Published: | 18 Feb 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39966646/ |
| DOI: | https://doi.org/10.1038/s41588-025-02087-4 |
| URL: | https://kclpure.kcl.ac.uk/portal/en/publications/e9698aea-6599-40b8-aa43-fd6173363911 |
Publication 15263
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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.</p>
13 Keywords
- Cardiomyopathy, Hypertrophic
- Case-Control Studies
- Female
- Genetic Loci
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Male
- Membrane Proteins
- Mendelian Randomization Analysis
- Microfilament Proteins
- Middle Aged
- Polymorphism, Single Nucleotide
62 Authors
- Rafik Tadros
- Sean L. Zheng
- Christopher Grace
- Paloma Jordà
- Catherine Francis
- Dominique M. West
- Sean J. Jurgens
- Kate L. Thomson
- Andrew R. Harper
- Elizabeth Ormondroyd
- Xiao Xu
- Pantazis I. Theotokis
- Rachel J. Buchan
- Kathryn A. McGurk
- Francesco Mazzarotto
- Beatrice Boschi
- Elisabetta Pelo
- Michael Lee
- Michela Noseda
- Amanda Varnava
- Alexa M. C. Vermeer
- Roddy Walsh
- Ahmad S. Amin
- Marjon A. van Slegtenhorst
- Nicole M. Roslin
- Lisa J. Strug
- Erika Salvi
- Chiara Lanzani
- Antonio de Marvao
- Jason D. Roberts
- Maxime Tremblay-Gravel
- Genevieve Giraldeau
- Julia Cadrin-Tourigny
- Philippe L. L'Allier
- Patrick Garceau
- Mario Talajic
- Sarah A. Gagliano Taliun
- Yigal M. Pinto
- Harry Rakowski
- Antonis Pantazis
- Wenjia Bai
- John Baksi
- Brian P. Halliday
- Sanjay K. Prasad
- Paul J. R. Barton
- Declan P. O'Regan
- Stuart A. Cook
- Rudolf A. de Boer
- Imke Christiaans
- Michelle Michels
- Christopher M. Kramer
- Carolyn Y. Ho
- Stefan Neubauer
- Paul M. Matthews
- Arthur A. M. Wilde
- Jean-Claude Tardif
- Iacopo Olivotto
- Arnon Adler
- Anuj Goel
- James S. Ware
- Connie R. Bezzina
- Hugh Watkins
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