Evidence of variations in genetic prevalence for loss-of-function PKP2 variants between individuals with European and...

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited condition associated with increased risk for ventricular arrhythmias and sudden cardiac death. Prior ARVC studies contained majority European-ancestry individuals; however, limited data have shown an increase in disease-associated variants in individuals of African ancestry. This study aimed to assess genotype/phenotype differences by ancestry across several cohorts.

We analyzed genomic and health record data from over 660,000 individuals from 4 population biobanks. We compared the prevalence of predicted pathogenic variants in 4 ARVC-associated genes across ancestries and the association with ARVC-related traits.

We observed that individuals with a PKP2 predicted pathogenic variant were 2 to 3 times as likely to be of African ancestry than European ancestry in MyCode, All of Us, and the UK Biobank. This difference was not seen in the Penn Medicine Biobank (PMBB). PKP2 predicted pathogenic heterozygotes were more likely to have an ARVC-related trait in the MyCode and All of Us cohorts but not in PMBB or UK Biobank.

Although individuals of African ancestry are more likely to carry a PKP2 predicted pathogenic variant, only European ancestry heterozygotes in MyCode and All of Us had increased odds of an ARVC-related trait, suggesting reduced penetrance or clinical underrecognition of disease in individuals of African ancestry.