Abstract 14515: Distinct Genetic Mechanisms for Bradyarrhythmias From Multi-Center Multi-Ancestry Meta-Analyses

Abstract

Background: With an increasing prevalence in older adults, bradyarrhythmias pose a major public health problem. Hypothesis: Genetics can inform on disease pathophysiology and implicate targets for therapeutic development for bradyarrhythmias. Methods: We first performed ancestry-specific genome-wide association studies (GWAS) and combined the results in meta-analyses of up to 1.3 million individuals including 9,511 sinus node dysfunction (SND) cases, 34,086 distal conduction disease (DCD) cases, and 28,899 pacemaker implantation (PM) cases. 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 (cases: 1,766 SND, 12,422 DCD & 5,646 PM) from UK Biobank and Mass General Brigham Biobank. Results: Common variant analyses identified 13, 28, and 21 loci for SND, DCD, and PM, respectively. SND and DCD were moderately genetically correlated (r g = 0.64). Common variant loci included genes underlying familial forms of bradyarrhythmias (HCN4 and SCN5A) and genes regulating population-level variation in electrocardiographic traits. 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 SND ( PITX2 , HCN4 , ZFHX3 ) or DCD ( CAV1 and NKX2 - 5 ). We observed an inverse association between predicted cardiac expression of SCN10A and risk of SND and DCD, and positive associations of predicted cardiac expression of CEP68 and STRN with risk of SND and DCD, respectively. Among 9 cardiac cell types, cardiomyocyte-expressed genes were enriched for contributions to DCD heritability. Rare variant analyses implicated LMNA for all bradyarrhythmia subtypes; SMAD6 and SCN5A for DCD; and TTN , MYBPC3 , and SCN5A for PM. Conclusions: We identify novel genes and loci associated with bradyarrhythmias. 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.