Journal
NATURE GENETICS
Volume 53, Issue 2, Pages 135-+Publisher
NATURE RESEARCH
DOI: 10.1038/s41588-020-00764-0
Keywords
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Categories
Funding
- British Heart Foundation (BHF)
- Medical Research Council (MRC)
- National Heart, Lung, and Blood Institute (NIH) [U01HL117006-01A1]
- Wellcome Trust [201543/B/16/Z, 090532/Z/09/Z, 203141/Z/16/Z]
- National Institute for Health Research (NIHR) Oxford Biomedical Research Centre
- MRC
- BHF
- European Commission [LSHM-CT-2007-037273, HEALTH-F2-2013-601456]
- Tripartite Immunometabolism Consortium (TrIC)-NovoNordisk Foundation [NNF15CC0018486]
- NIHR Barts Biomedical Research Centre
- Wellcome Trust
- Oxford BHF Centre of Research Excellence [RE/13/1/30181]
- Health Data Research UK
- NIHR Oxford Biomedical Research Centre
- NIHR
- NHS England
- Cancer Research UK
- National Health Service
- MRC [MC_UP_1102/20, 1964807] Funding Source: UKRI
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The study identified 12 genome-wide significant susceptibility loci for HCM, showing a strong polygenic influence, especially for sarcomere-negative HCM. A genetic risk score influenced the odds of HCM and phenotypic severity in carriers of sarcomere variants. Mendelian randomization identified diastolic blood pressure as a key modifiable risk factor for sarcomere-negative HCM.
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; h(g)(2) = 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.
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