From brain to heart: Causality and therapeutic potential in atrial fibrillation

To elucidate the causal relationship between resting-state brain function and atrial fibrillation (AF), and to pinpoint potential genetic targets and therapeutic compounds for AF.

Employing GTEx V8 eQTL and deCODE Genetics pQTL datasets, key genes associated with AF were identified through Mendelian Randomization (MR) and Summary-based Mendelian Randomization (SMR) analyses. Colocalization analysis was subsequently conducted to confirm the shared genetic loci influencing both brain function and AF. In addition, transcriptome differential expression and pathway enrichment analysis were undertaken to delineate the potential molecular mechanism. Drug screening and molecular docking are employed to evaluate the therapeutic efficacy of the candidate compounds.

MR Analysis revealed a significant causal relationship between resting-state brain functions of the default mode network (DMN) and central executive network (CEN) and AF. SMR and co-localization analyses identify the WIPF1 gene as a key genetic locus shared with brain function and AF. Candidate compounds C₁₂H₁₂N₄S, C₁₆H₁₅N₅O₂ and C₁₆H₁₃NO₆ showed anti-inflammatory and antibacterial properties, and exhibited good binding affinity in molecular docking, supporting their potential as therapeutic agents.

This study reveals a novel genetic association between resting-state brain function and AF and identifies WIPF1 as a potential therapeutic target, offering fresh insights into the study of brain-heart interaction and targeted treatment strategies for AF.