Objective:To investigate the relationship between lipid-modulating drugs and atrial fibrillation (AF).MethodsA causal association between total cholesterol (TC), total triglycerides (TG), low-density lipoproteins (LDL), high-density lipoproteins (HDL), apolipoprotein A1, and apolipoprotein B with AF was investigated initially using Mendelian randomization (MR). Drug-targeted MR and summary data-based Mendelian randomization (SMR) were used to investigate causal relationships between HMGCR, LPL, CETP, LDLR, PCSK9, and AF. A mediation MR analysis was also performed to assess the effect of HMGCR on AF through LDL.ResultsThe two MR analysis across the two datasets illustrated an inverse association between genetically predicted apolipoprotein A1 and AF risk [OR: 0.83 (95% CI 0.74-0.94)]. No significant causal links were found between TC, TG, LDL, HDL, and apolipoprotein B. An additional drug-targeted MR analysis found no significant causal relationships between HMGCR, LPL, CETP, LDLR, PCSK9. The SMR analysis determined that HMGCR was related to AF risk, whereas the mediation MR analysis did not indicate that HMGCR could cause AF via LDL.ConclusionThis study provides evidence for a negative association between genetically predicted ApoA1 and AF risk, whereas rs6453133 of the HMGCR gene may influence AF progression by modulating expression of the HMGCR locus, which needs further studies to be confirmed.