Common and Rare Variant Contributions to Bradyarrhythmias from Multi-Ancestry Meta-Analyses

ABSTRACT To broaden our understanding of bradyarrhythmias and diseases of the cardiac conduction system, we performed cross-sectional multi-ancestry genome-wide association study meta-analyses in up to 1.3 million individuals for sinus node dysfunction (SND), distal conduction disease (DCD), and pacemaker implantation (PM). We evaluated the biological relevance of bradyarrhythmia loci by analyses of transcriptomes, pleiotropy, and partitioned heritability based on cardiac single cell RNA sequencing data. Finally, we performed rare variant burden testing in 460,000 whole exome sequenced individuals from two biobanks. We identified 13, 28, and 21 common variant loci for SND, DCD, and PM, respectively. Four well-known common variant arrhythmia loci ( SCN5A/SCN10A , CCDC141, TBX20 , and CAMK2D) were shared for SND and DCD, while other loci were more specific for either SND or DCD. Cardiomyocyte-expressed genes were strongly enriched for contributions to DCD heritability, while SND and PM were more heterogeneous. Rare variant analyses implicated LMNA for all bradyarrhythmia subtypes; SMAD6 and SCN5A for DCD; and TTN , MYBPC3 , and SCN5A for PM. The genetic architectures of SND and DCD are both overlapping and distinct. Multiple genetic mechanisms involving ion channels, sarcomeric components, cellular homeostasis, and cardiac development may influence the development of bradyarrhythmias.