CEP68/FLRT2: The Potential Druggable Genes For Atrial Fibrillation Identified By Systematic Druggable Genome-Wide Mendelian Randomization

Background Atrial Fibrillation (AF), a globally prevalent arrhythmia with escalating incidence, still lacks effective treatments focusing on its substrate. Mendelian Randomization (MR) has been widely used to discover potential druggable targets. Thus, we aim to explore novel druggable targets for AF through MR analyses. Methods We conducted traditional and summary MR analysis integrating obtained druggable genes and AF genome-wide association data to examine the causal effect of cardiac (atrial/ventricular) and blood Expression Quantitative Trait Loci (eQTLs) and blood protein QTLs (pQTLs) on AF. A Phenome-Wide Association Study (PheWAS) was performed to find potential side effects. Results Twenty-one druggable genes were identified as potentially associated with AF (ALB, BAZ2A, CASQ2, CEP68, F10, FLRT2, GYPC, HABP4, JAM2, KCNJ5, KDM1B, PMVK, PRKD3, PROZ, PSMC5, PXN, SF3B1, THRB, TNNT3, TPMT, WDR1), two of which (CEP68 and FLRT2) were significant in both cardiac and blood tissue. Further, PheWAS showed that CEP68 was highly correlated with atrial fibrillation/flutter. Conclusion This study identified 21 potential druggable target genes for AF utilizing MR and SMR analyses, with 2 of them (CEP68 and FLRT2) showing significant associations in both cardiac tissue and blood. Our findings provide genetic evidence for these targets, which will be useful for AF drug development.