Harper, AR;
Goel, A;
Grace, C;
Thomson, KL;
Petersen, SE;
Xu, X;
Waring, A;
Ormondroyd, E;
Kramer, CM;
Ho, CY;
et al.
Harper, AR; Goel, A; Grace, C; Thomson, KL; Petersen, SE; Xu, X; Waring, A; Ormondroyd, E; Kramer, CM; Ho, CY; Neubauer, S; HCMR Investigators; Tadros, R; Ware, JS; Bezzina, CR; Farrall, M; Watkins, H
(2021)
Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity.
Nat Genet, 53 (2).
pp. 135-142.
ISSN 1546-1718
https://doi.org/10.1038/s41588-020-00764-0
SGUL Authors: Anderson, Lisa
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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.
Item Type: |
Article
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Additional Information: |
Harper, A.R., Goel, A., Grace, C. et al. Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity. Nat Genet 53, 135–142 (2021). |
Keywords: |
Adolescent, Adult, Aged, Blood Pressure, Cardiac Myosins, Cardiomyopathy, Hypertrophic, Carrier Proteins, Case-Control Studies, Formins, Genetic Predisposition to Disease, Genome-Wide Association Study, Heterozygote, Humans, Middle Aged, Myosin Heavy Chains, Polymorphism, Single Nucleotide, Risk Factors, Sarcomeres, Young Adult, Developmental Biology, 11 Medical and Health Sciences, 06 Biological Sciences |
SGUL Research Institute / Research Centre: |
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) |
Journal or Publication Title: |
Nat Genet |
ISSN: |
1546-1718 |
Language: |
eng |
Dates: |
Date | Event |
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February 2021 | Published | 25 January 2021 | Published Online | 14 December 2020 | Accepted |
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Publisher License: |
Publisher's own licence |
Projects: |
|
PubMed ID: |
33495597 |
Web of Science ID: |
WOS:000611467100003 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/113790 |
Publisher's version: |
https://doi.org/10.1038/s41588-020-00764-0 |
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