Genetic Association and Causal Effects Between Obesity and Multiple Sclerosis: A Robust Two-Sample Mendelian Randomization Study

Background: A relationship between obesity, as measured by body mass index (BMI), and multiple sclerosis (MS) has been reported in several observational studies. This study aimed to investigate the potential causal relationship between BMI and the risk of developing MS using a Mendelian randomization (MR) approach. Materials and methods: A two-sample MR analysis was performed using single nucleotide polymorphisms (SNPs) associated with the exposures - BMI and MS - sourced from publicly available genome-wide association studies (GWAS) at a genome-wide significance threshold of P = 5 × 10-8. The primary analytical methods included inverse-variance weighted (IVW), weighted median, MR-Egger, simple mode, and weighted mode approaches. Cochran's Q-test was applied to assess heterogeneity, while the MR-Egger intercept was used to detect potential horizontal pleiotropy. Sensitivity and robustness were evaluated through leave-one-out analysis. Additional methods - radial IVW, radial MR-Egger, MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO), MR-Least Absolute Shrinkage and Selection Operator (MR-LASSO), Generalized Summary-data-based Mendelian Randomization v2 (GSMR2), and MR-Robust Adjusted Profile Score (MR-RAPS) - were employed to estimate causal effects, assess instrument validity, and identify potential outlier SNPs. A P-value of less than 0.05 was considered statistically significant. Results: The MR analysis revealed a causal effect of BMI on MS as indicated by IVW (odds ratio (OR) = 1.39; 95% confidence interval (CI) = 1.23, 1.58; P = 1.42e-07), IVW method with modified second-order weights (IVW (Mod.2nd)) (OR = 1.39; 95% CI = 1.28, 1.51; P = 2.31e-15), MR-Egger (OR = 1.39; 95% CI = 1.01, 1.92; P = 4.51e-02), MR-Genotype Recoding Invariance Property (MR-GRIP) (OR = 1.41; 95% CI = 1.21, 1.65; P = 1.80e-05), MR-PRESSO (OR = 1.39; 95% CI = 1.28, 1.51; P = 3.79e-14), MR-RAPS (OR = 1.39; 95% CI = 1.24, 1.56; P = 2.66e-08), and GSMR (OR = 1.38; 95% CI = 1.23, 1.55; P = 3.35e-08). No evidence of horizontal pleiotropy or heterogeneity was detected, and the findings were confirmed to be robust. Conclusion: This study provides evidence that an increase in body size (BMI) can lead to MS. Therefore, maintaining a healthy weight during early life could be a potential strategy to reduce MS risk.