Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity
File(s)
Supporting information
Accepted version
Author(s)
Type
Journal Article
Abstract
Hypertrophic cardiomyopathy (HCM) is a common, serious, genetic heart disorder. Rare pathogenic variants in sarcomere genes cause HCM, but with unexplained phenotypic heterogeneity. Moreover, most patients do not carry such variants. We report a genome-wide association study of 2,780 cases and 47,486 controls that identified 12 genome-wide-significant susceptibility loci for HCM. Single-nucleotide polymorphism heritability indicated a strong polygenic influence, especially for sarcomere-negative HCM (64% of cases; h2g = 0.34 ± 0.02). A genetic risk score showed substantial influence on the odds of HCM in a validation study, halving the odds in the lowest quintile and doubling them in the highest quintile, and also influenced phenotypic severity in sarcomere variant carriers. Mendelian randomization identified diastolic blood pressure (DBP) as a key modifiable risk factor for sarcomere-negative HCM, with a one standard deviation increase in DBP increasing the HCM risk fourfold. Common variants and modifiable risk factors have important roles in HCM that we suggest will be clinically actionable.
Date Issued
2021-01-25
Date Acceptance
2020-12-14
Citation
Nature Genetics, 2021, 53, pp.135-142
ISSN
1061-4036
Publisher
Nature Research
Start Page
135
End Page
142
Journal / Book Title
Nature Genetics
Volume
53
Copyright Statement
© Crown 2021.
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000611467100003&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
GENOME-WIDE ASSOCIATION
SYSTOLIC HYPERTENSION
AMERICAN-COLLEGE
LOCI
GENOTYPE
DISCOVERY
DISEASE
Publication Status
Published
Date Publish Online
2021-01-25