Evaluation of polygenic scores for hypertrophic cardiomyopathy in the general population and across clinical settings
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Published version
Author(s)
Type
Journal Article
Abstract
Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality, with pathogenic variants found in about a third of cases. Large-scale genome-wide association studies (GWAS) demonstrate that common genetic variation contributes to HCM risk. Here we derive polygenic scores (PGS) from HCM GWAS and genetically correlated traits and test their performance in the UK Biobank, 100,000 Genomes Project, and clinical cohorts. We show that higher PGS significantly increases the risk of HCM in the general population, particularly among pathogenic variant carriers, where HCM penetrance differs 10-fold between those in the highest and lowest PGS quintiles. Among relatives of HCM probands, PGS stratifies risks of developing HCM and adverse outcomes. Finally, among HCM cases, PGS strongly predicts the risk of adverse outcomes and death. These findings support the broad utility of PGS across clinical settings, enabling tailored screening and surveillance and stratification of risk of adverse outcomes.
Date Issued
2025-03-01
Date Acceptance
2025-01-21
Citation
Nature Genetics, 2025, 57 (3)
ISSN
1061-4036
Publisher
Nature Research
Journal / Book Title
Nature Genetics
Volume
57
Issue
3
Copyright Statement
© The Author(s) 2025 Open Access 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/39966645
PII: 10.1038/s41588-025-02094-5
Subjects
AMERICAN-COLLEGE
COMPLEX TRAITS
DIAGNOSIS
GENETICS
Genetics & Heredity
GENOME-WIDE ASSOCIATION
GUIDELINES
IMPUTATION
Life Sciences & Biomedicine
PREVALENCE
RISK
Science & Technology
VARIANTS
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2025-02-18