Negative emotions mediate the causal association between GERD and MG: A mediation Mendelian randomization study

Emerging evidence suggests a potential link between gastroesophageal reflux disease (GERD) and autoimmune disorders, yet the causal effect of GERD on myasthenia gravis (MG) remains unclear. Psychological factors, particularly negative emotions, have been implicated in both GERD and MG pathogenesis, raising the possibility that they may mediate this association. This study aims to elucidate the bidirectional causal relationship between GERD and MG, explore its subtype-specific effects, and investigate the mediating role of negative emotions through Mendelian randomization (MR) approach. Univariate MR (UVMR) was conducted to assess the bidirectional causal association between GERD and MG, with additional stratified analyses for its subtypes. Multivariable MR (MVMR) was then performed to evaluate the independent effect of GERD on MG after adjusting for body mass index. Finally, mediation analysis was employed to determine whether negative emotions mediated the effect of GERD on MG. UVMR analysis demonstrated that GERD significantly increased the risk of MG (ORIVW, 1.47; 95% CI, 1.10-1.97; P = .009), whereas MG had no causal effect on GERD (ORIVW, 1.01; 95% CI, 0.98-1.03; P = .635). Subgroup analysis revealed a significant association between GERD and late-onset MG (ORIVW, 1.47; 95% CI, 1.03-2.08; P = .033) but no evident link with early-onset MG (ORIVW, 0.90; 95% CI, 0.49-1.64; P = .727). MVMR analysis indicated that the causal effect of GERD on MG remained robust after adjusting for body mass index (ORIVW, 1.48; 95% CI, 1.05-2.09; P = .027). Mediation analysis further identified Fed-up feelings as a significant mediator in the GERD-MG pathway (mediation proportion [95% CI]: 49.4% (10.6%-88.2%], P = .012), whereas worrier/anxious feelings (mediation proportion [95% CI]: 7.2% [-6.3% to 20.7%], P = .278) and depression (mediation proportion [95% CI]: -25.0% [-103.2% to 53.1%], P = .530) did not exhibit significant mediation effects. This study provides robust genetic evidence supporting GERD as a potential causal risk factor for MG and, for the first time, highlights Fed-up feelings as a key mediator in this relationship. These findings underscore the importance of psychological factors in the pathogenesis of GERD-associated MG and suggest that targeting emotional well-being may offer novel strategies for disease prevention and management.