Causal Impact of Genetically Predicted Leptin Levels on Atrial Fibrillation Risk: Evidence from Bidirectional Mendelian Randomization Analysis

Background: Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia, contributing substantially to global morbidity and mortality. Although adiposity-related adipokines such as leptin have been associated with AF, the causal direction and independence from confounding factors remain uncertain. Methods: We applied a bidirectional two-sample Mendelian randomization (MR) framework to assess the causal relationship between genetically predicted circulating leptin levels and AF risk. Genetic instruments for leptin were obtained from BMI-adjusted genome-wide association studies (GWAS), and AF summary statistics were sourced from large-scale meta-analyses. Causal estimates were derived using inverse variance-weighted (IVW), weighted median, and MR-robust adjusted profile score (MR-RAPS) methods. Reverse MR and sensitivity analyses were conducted to evaluate directionality and robustness. Results: Genetically predicted elevated leptin levels were significantly associated with increased AF risk (IVW OR = 1.18, 95% CI: 1.05-1.32, p = 0.005), supported by weighted median (OR = 1.24, 95% CI: 1.07-1.43, p = 0.004) and MR-RAPS (OR = 1.18, 95% CI: 1.05-1.33, p = 0.007) analyses. Reverse MR showed no evidence of a causal effect of AF on leptin levels. Sensitivity analyses confirmed the consistency and robustness of the findings. Conclusion: This study provides genetic evidence supporting a unidirectional causal effect of elevated leptin levels on AF risk, independent of adiposity. While these findings highlight leptin as a potential biomarker for AF susceptibility, further mechanistic and translational research is warranted to explore its role in atrial remodeling and therapeutic targeting.