Background: There is contradictory information about the involvement of leptin in atrial fibrillation (AF). Using a two-sample Mendelian randomization approach, we attempted to investigate the causative role of circulating leptin in AF. Methods: From previously reported genome-wide association studies, single nucleotide polymorphisms (SNPs) independently and singularly predictive of log-transformed leptin (rs1260326, rs13389219, rs4731702, rs791600, and rs900399) were obtained. We found correlations between leptin and AF by combining Wald estimates for each SNP and applying inverse variance weighting. The weighted median and MR-RAPS approaches were used in the sensitivity analysis. Results: Genetically predicted circulating leptin levels were associated with AF, with an odds ratio (OR) of 1.18 and a 95% confidence interval (CI) of 1.05–

1.32. The results of our sensitivity studies supported our conclusions. Conclusions: This is the first Mendelian randomization study estimating leptin’s causal effect on AF. Overall, our findings support the hypothesis that elevated levels of leptin are a risk factor for AF.