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| Item Type: | Letter |
|---|---|
| Title: | Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy |
| Creators Name: | Tadros, Rafik, Zheng, Sean L., Grace, Christopher, Jordà, Paloma, Francis, Catherine, West, Dominique M., Jurgens, Sean J., Thomson, Kate L., Harper, Andrew R., Ormondroyd, Elizabeth, Xu, Xiao, Theotokis, Pantazis I., Buchan, Rachel J., McGurk, Kathryn A., Mazzarotto, Francesco, Boschi, Beatrice, Pelo, Elisabetta, Lee, Michael, Noseda, Michela, Varnava, Amanda, Vermeer, Alexa M.C., Walsh, Roddy, Amin, Ahmad S., van Slegtenhorst, Marjon A., Roslin, Nicole M., Strug, Lisa J., Salvi, Erika, Lanzani, Chiara, de Marvao, Antonio, Roberts, Jason D., Tremblay-Gravel, Maxime, Giraldeau, Genevieve, Cadrin-Tourigny, Julia, L'Allier, Philippe L., Garceau, Patrick, Talajic, Mario, Gagliano Taliun, Sarah A., Pinto, Yigal M., Rakowski, Harry, Pantazis, Antonis, Bai, Wenjia, Baksi, John, Halliday, Brian P., Prasad, Sanjay K., Barton, Paul J.R., O'Regan, Declan P., Cook, Stuart A., de Boer, Rudolf A., Christiaans, Imke, Michels, Michelle, Kramer, Christopher M., Ho, Carolyn Y., Neubauer, Stefan, Matthews, Paul M., Wilde, Arthur A.M., Tardif, Jean-Claude, Olivotto, Iacopo, Adler, Arnon, Goel, Anuj, Ware, James S., Bezzina, Connie R. 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. |
| Keywords: | Case-Control Studies, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Hypertrophic Cardiomyopathy, Membrane Proteins, Mendelian Randomization Analysis, Microfilament Proteins, Single Nucleotide Polymorphism |
| Source: | Nature Genetics |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Volume: | 57 |
| Number: | 3 |
| Page Range: | 530-538 |
| Date: | March 2025 |
| Additional Information: | Jeanette Schulz-Menger is an HCMR Investigator. |
| Official Publication: | https://doi.org/10.1038/s41588-025-02087-4 |
| PubMed: | View item in PubMed |
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