Identification of novel therapeutic targets for atrial fibrillation through Mendelian randomization analysis of druggable genes

BACKGROUND: Innovative therapeutic approaches are essential for treating atrial fibrillation (AF), yet genetic support for AF-specific drug targets remains limited. METHODS: This Mendelian randomization (MR) study employed cis-expression quantitative trait loci (cis-eQTLs) to assess the causal relationships between gene expression and AF. After achieving significance in the UK Biobank following multiple testing adjustments and validation in FinnGen, colocalization analysis and protein quantitative trait loci (pQTL) analysis were carried out. RESULTS: In the UK Biobank, genetic expression of 65 genes showed significant correlation with AF risk, and 15 were replicated in FinnGen. Colocalization analysis identified three primary candidates: WDR1, ESR2, and CXCL10, with significant associations in inverse variance-weighted (IVW) analysis. ESR2 showed a positive association with AF (OR = 1.403; 95 % CI: 1.200-1.640), while WDR1 (OR = 0.800; 95 % CI: 0.734-0.871) and CXCL10 (OR = 0.814; 95 % CI: 0.738-0.897) were negatively associated. Given the absence of pQTL data for ESR2 and WDR1, pQTL analysis focused exclusively on CXCL10 (OR = 0.59; 95 % CI: 0.43-0.82). Results from both the MR-Egger and weighted median methods were predominantly in agreement with that from IVW analyses. CONCLUSION: ESR2, WDR1 and CXCL10 emerge as promising therapeutic targets for AF.