Proteome-wide Mendelian randomization and colocalization analyses identify novel protein targets for cardiac conduction disorders.

Background: The occurrence and progression of cardiac conduction disorder (CCD) pose a significant threat to people's health. However, current pharmacological treatments for CCD are relatively limited, with few mechanistic studies and intervention strategies.

Methods: We derived protein quantitative trait loci from two comprehensive databases: UKBPPP and deCODE Health study. Genetic associations with CCD and its subsets were obtained from the FinnGen R11 database. Summary-data-based Mendelian randomization and colocalization analyses were conducted to identify potential protein targets. Phenome-wide association study (PheWAS), multivariable Mendelian randomization (MVMR), and multi-omic analyses were further performed to elucidate the underlying biological mechanisms of the identified protein targets.

Results: Genetically predicted CASP9 (OR: 2.65, 95 % CI: 1.65 to 4.26, p_FDR = 0.007) and ASPH (OR: 2.03, 95 % CI: 1.32 to 3.11, p_FDR = 0.024) were significantly associated with a higher risk of atrioventricular block, while genetically predicted SRA1 (OR: 0.54, 95 % CI: 0.39 to 0.75, p_FDR = 0.009) was markedly associated with a lower risk of atrioventricular block. Additionally, the protein CFHR5 (OR: 0.82, 95 % CI: 0.70 to 0.96, p_FDR = 0.157) was linked to a decreased incidence of left bundle branch block with suggestive significance. PheWAS and MVMR analyses suggested that hyperkalemia may serve as a potential mediating pathway between CASP9 and atrioventricular block. Multi-omics analysis revealed several methylation sites of CASP9 linked with atrioventricular block.

Conclusion: We identified several novel protein targets for CCD and uncovered their underlying biological processes.