TY - JOUR
T1 - Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy
AU - Hypergenes InterOmics Collaborators
AU - HCMR Investigators
AU - Tadros, Rafik
AU - Zheng, Sean L.
AU - Grace, Christopher
AU - Jordà, Paloma
AU - Francis, Catherine
AU - West, Dominique M.
AU - Jurgens, Sean J.
AU - Thomson, Kate L.
AU - Harper, Andrew R.
AU - Ormondroyd, Elizabeth
AU - Xu, Xiao
AU - Theotokis, Pantazis I.
AU - Buchan, Rachel J.
AU - McGurk, Kathryn A.
AU - Mazzarotto, Francesco
AU - Boschi, Beatrice
AU - Pelo, Elisabetta
AU - Lee, Michael
AU - Noseda, Michela
AU - Varnava, Amanda
AU - Vermeer, Alexa M.C.
AU - Walsh, Roddy
AU - Amin, Ahmad S.
AU - van Slegtenhorst, Marjon A.
AU - Roslin, Nicole M.
AU - Strug, Lisa J.
AU - Salvi, Erika
AU - Lanzani, Chiara
AU - de Marvao, Antonio
AU - Glorioso, Nicola
AU - Citterio, Lorena
AU - Manunta, Paolo
AU - Cusi, Daniele
AU - Roberts, Jason D.
AU - Tremblay-Gravel, Maxime
AU - Giraldeau, Genevieve
AU - Cadrin-Tourigny, Julia
AU - L’Allier, Philippe L.
AU - Garceau, Patrick
AU - Talajic, Mario
AU - Gagliano Taliun, Sarah A.
AU - Pinto, Yigal M.
AU - Rakowski, Harry
AU - Pantazis, Antonis
AU - Bai, Wenjia
AU - Baksi, John
AU - Halliday, Brian P.
AU - Prasad, Sanjay K.
AU - Plein, Sven
AU - Chiribiri, Amedeo
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/3
Y1 - 2025/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85218269559&partnerID=8YFLogxK
U2 - 10.1038/s41588-025-02087-4
DO - 10.1038/s41588-025-02087-4
M3 - Article
C2 - 39966646
AN - SCOPUS:85218269559
SN - 1061-4036
VL - 57
SP - 530
EP - 538
JO - Nature Genetics
JF - Nature Genetics
IS - 3
M1 - 1826
ER -