Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy
Author(s)
Type
Journal Article
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.
Date Issued
2025-03-01
Date Acceptance
2025-01-10
Citation
Nature Genetics, 2025, 57 (3), pp.530-538
ISSN
1061-4036
Publisher
Nature Research
Start Page
530
End Page
538
Journal / Book Title
Nature Genetics
Volume
57
Issue
3
Copyright Statement
© The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/39966646
Source
Annual Meeting of the European-Society-of-Cardiology (ESC)
Subjects
CONTRACTILITY
Genetics & Heredity
GROWTH
HCM
Life Sciences & Biomedicine
MODEL
MUSCLE
RISK
Science & Technology
SKELETAL
VARIANTS
Publication Status
Published
Start Date
2023-08-25
Finish Date
2023-08-28
Coverage Spatial
NETHERLANDS, Amsterdam
Date Publish Online
2025-02-18