Rare and Common Genetic Variation Underlying the Risk of Hypertrophic Cardiomyopathy in a National Biobank

Abstract

Importance: Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death in young people. Although rare genetic variants are well-established contributors to HCM risk, common genetic variants have recently been implicated in disease pathogenesis.

Objective: To assess the contributions of rare and common genetic variation to risk of HCM in the general population.

Design, setting, and participants: This cohort study of the UK Biobank (data from 2006-2010) and the Mass General Brigham Biobank (2010-2019) assessed the relative and joint contributions of rare genetic variants and a common variant (polygenic) score to risk of HCM. Both rare and common variant predictors were then evaluated in the context of relevant clinical risk factors. Data analysis was conducted from May 2021 to February 2022.

Exposures: Pathogenic rare variants, common-variant (polygenic) score, and clinical risk factors.

Main outcomes and measures: Risk of HCM.

Results: The primary study population comprised 184 511 individuals from the UK Biobank. Mean (SD) age was 56 (8) years, 83 690 (45%) of participants were men, and 204 (0.1%) participants had HCM. Of 51 genes included in clinical genetic testing panels for HCM, pathogenic or likely pathogenic variants in 14 core genes (designated by the American College of Medical Genetics and Genomics [ACMG]) were associated with 55-fold higher odds (95% CI, 35-83) of HCM, while those in the remaining 37 non-ACMG genes were not significantly associated with HCM (OR, 1.8; 95% CI, 0.6-4.0). ClinVar pathogenic or likely pathogenic mutations in MYBPC3 (OR, 72; 95% CI, 39-124) and MYH7 (OR, 61; 95% CI, 26-121) were strongly associated with HCM, as were loss-of-function variants in ALPK3 (OR, 13; 95% CI, 4.4-28). A polygenic score was strongly associated with HCM (OR per SD increase in score, 1.6; 95% CI, 1.4-1.8), with concordant results in the Mass General Brigham Biobank. Genetic factors enhanced clinical risk prediction for HCM: addition of rare variant carrier status and the polygenic score to clinical risk factors (obesity, hypertension, atrial fibrillation, and coronary artery disease) improved the area under the receiver operator characteristic curve from 0.71 (95% CI, 0.65-0.77) to 0.82 (95% CI, 0.77-0.87).

Conclusions and relevance: Both rare and common genetic variants contribute substantially to HCM susceptibility in the general population and improve HCM risk prediction beyond that achieved with clinical factors.

Figure 1.. Lifetime Risk of Hypertrophic Cardiomyopathy (HCM) by Rare Variant Carrier Status and Strata of Polygenic Risk

A, Lifetime risk of HCM, defined as the percent chance of a diagnosis of hypertrophic cardiomyopathy by age 80 years (n = 129 incident cases), in strata of rare variant carrier status and polygenic risk. B, Cumulative incidence plots for HCM in strata of rare variant carrier status and polygenic risk. Rare variant carrier status was defined as the presence of an HCM–American College of Medical Genetics and Genomics (ACMG) variant. Low polygenic risk was defined as the lowest quintile, intermediate risk as quintiles 2 through 4, and high risk as the top quintile of the polygenic risk score (PRS) distribution. Error bars denote 95% CI. Data analysis was conducted in the UK Biobank.

Figure 2.. Comparisons of Individual Genetic and Nongenetic Risk Factors for Hypertrophic Cardiomyopathy (HCM)

A, Hazard ratios for HCM (n = 129 incident cases), calculated using Cox proportional-hazards models adjusting for age, sex, genotyping array, and principal components 1 through 5. B, Proportion of population-wide HCM susceptibility explained by genetic and nongenetic risk factors. High polygenic risk is defined as a score in the top quintile of polygenic risk score (PRS) distribution. Error bars denote 95% CI. Data analysis was conducted in the UK Biobank. ACMG indicates American College of Medical Genetics and Genomics; AF, atrial fibrillation; CAD, coronary artery disease.

Figure 3.. Cumulative Performance of Genetic and Nongenetic Risk Factors for Hypertrophic Cardiomyopathy (HCM)

A, Cumulative area under the receiver operator characteristic curve (AUC) for HCM (n = 129 incident cases). The vertical line represents the AUC for the baseline logistic regression model inclusive of age, sex, and principal components (PCs) 1 through 5. Clinical and genetic factors were then added sequentially as predictors on top of the baseline model. B, Cumulative variance in disease susceptibility explained. Plotted values are calculated as improvement in r² on the liability scale on adding risk factors to a logistic regression model consisting of age, sex, and PCs 1-5 in a stepwise fashion. High polygenic risk is defined as an individual with a score in the top quintile of polygenic risk score (PRS) distribution. Data analysis was conducted in the UK Biobank. Error bars denote 95% CI. ACMG indicates American College of Medical Genetics and Genomics; AF, atrial fibrillation; CAD, coronary artery disease; HTN, hypertension.