Association of Common Ancestry-Enriched Variants With Cardiomyopathy and Arrhythmias
Year: 2026
Type: article
Study design: Observational Study
Abstract: 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.
Source: Circulation
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Pharmacogenomics of Arrhythmia Therapy, Illinois Precision Medicine Consortium , Understanding the genetic risk underlying racial disparities in uterine fibroids, Improving Prediction of Drug Action, Automated Storage and Retrieval of Biological Systems, Technology to Empower Changes in Health (TECH) Network Participant Technologies Center, University of Arizona-Banner Health All of Us Research Program , Genetic Epidemiology of Multiple Sclerosis, All of Us Pennsylvania, The Vanderbilt Institute for Clinical and Translational Research (VICTR) UL1, VESPA: Vanderbilt Electronic Systems for Pharmacogenomic Assessment, The Vanderbilt Institute for Clinical and Translational Research (VICTR), Vanderbilt Genome Electronic Records Project, Epidemiologic Architecture for Genes Linked to Environment (EAGLE), Vanderbilt Institute for Clinical and Translational Research (VICTR)
OpenAlex ID: W7162544994