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, pFDR = 0.007) and ASPH (OR: 2.03, 95 % CI: 1.32 to 3.11, pFDR = 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, pFDR = 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, pFDR = 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.