Hypertrophic Cardiomyopathy Genetics
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Hypertrophic cardiomyopathy (HCM) is one of the most common, serious, genetic heart disorders. 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 revealed 12 genome-wide significant susceptibility loci for HCM. SNP-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 odds of HCM in a validation study, halving odds in the lowest quintile and doubling in the highest quintile, and also influenced phenotypic severity in sarcomere variant carriers. Mendelian randomisation revealed diastolic blood pressure (DBP) as a key modifiable risk factor for sarcomere-negative HCM; 1 SD increase in DBP increased HCM risk four-fold. Common variants, and modifiable risk factors, have important roles in HCM that we suggest will be clinically actionable.
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Email: Prof Hugh Watkins