| Title: |
Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy |
| Authors: |
Tadros, R; Zheng, SL; Grace, C; Jorda, P; Francis, C; West, DM; Jurgens, SJ; Thomson, KL; Harper, AR; Ormondroyd, E; Xu, X; Theotokis, PI; Buchan, RJ; Mcgurk, KA; Mazzarotto, F; Boschi, B; Pelo, E; Lee, M; Noseda, M; Varnava, A; Vermeer, AMC; Walsh, R; Amin, AS; van Slegtenhorst, MA; Roslin, NM; Strug, LJ; Salvi, E; Lanzani, C; de Marvao, A; Roberts, JD; Tremblay-Gravel, M; Giraldeau, G; Cadrin-Tourigny, J; L'Allier, PL; Garceau, P; Talajic, M; Gagliano Taliun, SA; Pinto, YM; Rakowski, H; Pantazis, A; Bai, W; Baksi, J; Halliday, BP; Prasad, SK; Barton, PJR; O'Regan, DP; Cook, SA; de Boer, RA; Christiaans, I; Michels, M; Kramer, CM; Ho, CY; Neubauer, S; Matthews, PM; Wilde, AAM; Tardif, J-C; Olivotto, I; Adler, A; Goel, A; Ware, JS; Bezzina, CR; Watkins, H |
| Publisher Information: |
Nature Research |
| Publication Year: |
2025 |
| Collection: |
St George's University of London: Repository |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf; application/msword |
| Language: |
English |
| ISSN: |
1061-4036 |
| Relation: |
https://openaccess.sgul.ac.uk/id/eprint/117276/1/s41588-025-02087-4.pdf; https://openaccess.sgul.ac.uk/id/eprint/117276/3/41588_2025_2087_MOESM1_ESM.pdf; https://openaccess.sgul.ac.uk/id/eprint/117276/5/41588_2025_2087_MOESM2_ESM.pdf; https://openaccess.sgul.ac.uk/id/eprint/117276/7/41588_2025_2087_MOESM3_ESM.pdf; https://openaccess.sgul.ac.uk/id/eprint/117276/8/41588_2025_2087_MOESM4_ESM.xlsx; Tadros, R; Zheng, SL; Grace, C; Jorda, P; Francis, C; West, DM; Jurgens, SJ; Thomson, KL; Harper, AR; Ormondroyd, E; et al. Tadros, R; Zheng, SL; Grace, C; Jorda, P; Francis, C; West, DM; Jurgens, SJ; Thomson, KL; Harper, AR; Ormondroyd, E; Xu, X; Theotokis, PI; Buchan, RJ; Mcgurk, KA; Mazzarotto, F; Boschi, B; Pelo, E; Lee, M; Noseda, M; Varnava, A; Vermeer, AMC; Walsh, R; Amin, AS; van Slegtenhorst, MA; Roslin, NM; Strug, LJ; Salvi, E; Lanzani, C; de Marvao, A; Roberts, JD; Tremblay-Gravel, M; Giraldeau, G; Cadrin-Tourigny, J; L'Allier, PL; Garceau, P; Talajic, M; Gagliano Taliun, SA; Pinto, YM; Rakowski, H; Pantazis, A; Bai, W; Baksi, J; Halliday, BP; Prasad, SK; Barton, PJR; O'Regan, DP; Cook, SA; de Boer, RA; Christiaans, I; Michels, M; Kramer, CM; Ho, CY; Neubauer, S; Matthews, PM; Wilde, AAM; Tardif, J-C; Olivotto, I; Adler, A; Goel, A; Ware, JS; Bezzina, CR; Watkins, H (2025) Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy. NATURE GENETICS, 57 (3). pp. 530-538. ISSN 1061-4036 https://doi.org/10.1038/s41588-025-02087-4 SGUL Authors: Walsh, Roderick Thomas |
| DOI: |
10.1038/s41588-025-02087-4 |
| Availability: |
https://openaccess.sgul.ac.uk/id/eprint/117276/; https://openaccess.sgul.ac.uk/id/eprint/117276/3/41588_2025_2087_MOESM1_ESM.pdf; https://openaccess.sgul.ac.uk/id/eprint/117276/5/41588_2025_2087_MOESM2_ESM.pdf; https://openaccess.sgul.ac.uk/id/eprint/117276/7/41588_2025_2087_MOESM3_ESM.pdf; https://openaccess.sgul.ac.uk/id/eprint/117276/8/41588_2025_2087_MOESM4_ESM.xlsx; https://doi.org/10.1038/s41588-025-02087-4 |
| Rights: |
cc_by_4 |
| Accession Number: |
edsbas.E555F646 |
| Database: |
BASE |