Association of Common Ancestry-Enriched Variants With Cardiomyopathy and Arrhythmias

BACKGROUND: Individuals of African ancestry are underrepresented in genetic studies, contributing to disproportionately higher rates of variants of uncertain significance (VUS) and fewer actionable results in genetic testing for cardiomyopathies and arrhythmias. We aimed to determine whether ancestry-enriched VUS confer measurable cardiovascular risk among individuals of African ancestry. METHODS: We identified VUS enriched in individuals of African ancestry in 18 cardiomyopathy and arrhythmia genes. We defined enriched as allele frequency in gnomAD ≥2-fold higher than in European (non-Finnish) individuals, and we confined the analysis to VUS with allele frequency >0.05% in individuals of African ancestry. Associations with cardiovascular phenotypes were assessed in 96 897 individuals of African ancestry from the All of Us (n=65 481) and BioVU (n=31 416) biobanks using fixed-effects meta-analysis. Analyses were stratified by heart failure (HF) status and conventional cardiovascular risk factors. RESULTS: We identified 82 ancestry-enriched VUS. Exploratory analysis in All of Us identified 10 variants associated with composite cardiovascular outcome, 4 of which were associated with individual cardiovascular phenotypes in pooled meta-analysis across both cohorts. PKP2 p.Val558Ile was associated with a 4-fold increased risk of ventricular arrhythmias or sudden cardiac death (adjusted odds ratio [aOR], 4.02 [95% CI, 1.85–8.71]; P =0.004). ELAC2 p.Ile396Val was associated with HF (aOR, 1.67 [95% CI, 1.17–2.39]; P =0.02) and atrial arrhythmias (aOR, 1.88 [95% CI, 1.27–2.78]; P =0.02). FLNC p.Gly11Ser and PKP2 p.Val842Ile were associated with HF (aOR, 1.96 [95% CI, 1.24–3.10]; P =0.02 and aOR, 1.99 [95% CI, 1.16–3.41]; P =0.039). The presence of cardiovascular risk factors was associated with earlier onset of HF (adjusted hazard ratio, 1.71 [95% CI, 1.25–2.33]; P =0.0006) and atrial arrhythmias (adjusted hazard ratio, 1.17 [95% CI, 1.06–1.29]; P =0.0019) in pooled variant carriers. PKP2 p.Val558Ile, SCN5A p.Gln1832Glu, and FLNC p.Gly11Ser demonstrated increased arrhythmia burden specifically in participants with HF. Using American College of Medical Genetics and Genomics guidelines, PKP2 p.Val558Ile met criteria for likely pathogenic classification, potentially affecting an estimated 24 000 Black adults in the United States. CONCLUSIONS: Large-scale biobank analysis identified variants classified as VUS that conferred increased risk of cardiomyopathy and arrhythmia in individuals with African ancestry. The risk associated with these variants was increased in the presence of cardiovascular risk factors and HF.