Association of programmed cell death with atrial fibrillation risk: A multi-omics Mendelian randomization study

The association between programmed cell death (PCD) and atrial fibrillation (AF), as well as the underlying genetic mechanisms, remains unclear. This study aimed to evaluate the causal relationships between PCD-related genes and AF using a multi-omics approach, involving Mendelian randomization (MR) and colocalization analyses. Genome-wide association studies summary statistics regarding PCD-related gene methylation, gene expression, and protein abundance were acquired from relevant studies, and 1073 PCD-related genes were analyzed. The reliability of the MR estimates was evaluated through colocalization analysis complemented by Steiger directionality test. At the methylation level, 568 cytosine-phosphate-guanine sites were mapped to 260 PCD-related genes with significant causal associations with AF. Notably, 333 genes were associated with AF risk at the expression level, and 95 plasma proteins were causally related to AF. By integrating evidence from multi-omics, we identified 8 tier 1 genes with strong multi-omics evidence. Furthermore, 3 and 27 genes were identified as AF tier 2 and 3 genes, respectively. This study provides compelling evidence of the involvement of PCD in the pathogenesis of AF, thereby advancing our understanding of the mechanism underlying AF. The identification of PCD-related genes linked to AF highlights their potential as diagnostic and therapeutic targets.