The Causal Relationship between Obesity and Myasthenia Gravis: A Two-Sample and Multivariate Study

Background Observational studies have identified a correlation between obesity and myasthenia gravis. Nonetheless, the causality of this relationship is debated. To address this, we employed Two-sample Mendelian Randomization (MR) to investigate the causal influences of obesity-related metrics on myasthenia gravis and its subtypes. Methods We retrieved the summary statistics of exposure-related single nucleotide polymorphisms (SNPs) from publicly available genome-wide association study abstracts, and the aggregate data of myasthenia gravis and its subtypes came from the largest genome-wide association studies, to conduct univariate and multivariate MR analyses. In the primary MR analysis, we used the inverse variance weighted (IVW) method, followed by weighted median, mode-based estimation, and MR-Egger regression. We further assessed the robustness of the results through a series of sensitivity analyses including MR pleiotropy residual sum and outlier (MR-PRESSO) test to detect the stability of the outcomes. Reverse MR analysis was also performed. Results Analysis revealed that obesity-related body composition metrics were initially linked to a heightened risk of myasthenia gravis. However, subsequent adjustments revealed that only hip circumference (Inverse Variance Weighted Odds Ratio (IVW OR = 1.67, 95% CI: 1.29 to 2.71, P < 0.001) and whole body fat mass (IVW OR = 1.60, 95% CI: 1.22 to 2.09, P < 0.001) exerted a significant detrimental causal effect on myasthenia gravis. In contrast, other obesity-related metrics did not demonstrate an increased risk for Late-Onset Myasthenia Gravis (LOMG) (IVW OR = 1.65, 95% CI: 1.22 to 2.24, P = 0.001), nor did obesity correlate with an increased risk of Early-Onset Myasthenia Gravis (EOMG). Further adjustments for genetic predisposition to diabetes in the multivariate analysis affirmed the significant association between hip circumference, whole body fat mass, and both types of myasthenia gravis. Additionally, reverse Mendelian Randomization analysis indicated that EOMG might elevate the risk associated with arm and leg fat mass. Conclusion Our findings reinforce the concept that obesity detrimentally influences myasthenia gravis, underscoring the imperative of incorporating obesity management into therapeutic strategies for this condition. Prospective investigations are essential to delineate the efficacy of obesity intervention in the prophylaxis of myasthenia gravis.