Almosallam Abdulaziz
Internal Medicine, Majmaah University, Al Majma'ah, SAU.
Cureus. 2025 Aug 3;17(8):e89287. doi: 10.7759/cureus.89287. eCollection 2025 Aug.
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.
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 = 5 × 10. 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 -value of less than 0.05 was considered statistically significant.
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.
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.
多项观察性研究报告了以体重指数（BMI）衡量的肥胖与多发性硬化症（MS）之间的关系。本研究旨在采用孟德尔随机化（MR）方法调查BMI与患MS风险之间的潜在因果关系。
使用与暴露因素（BMI和MS）相关的单核苷酸多态性（SNP）进行两样本MR分析，这些SNP来自公开可用的全基因组关联研究（GWAS），全基因组显著性阈值为 = 5 × 10。主要分析方法包括逆方差加权（IVW）、加权中位数、MR-Egger、简单模式和加权模式方法。应用Cochran's Q检验评估异质性，同时使用MR-Egger截距检测潜在的水平多效性。通过留一法分析评估敏感性和稳健性。采用其他方法——径向IVW、径向MR-Egger、MR-多效性残差和异常值（MR-PRESSO）、MR-最小绝对收缩和选择算子（MR-LASSO）、基于广义汇总数据的孟德尔随机化v2（GSMR2）以及MR-稳健调整轮廓评分（MR-RAPS）——来估计因果效应、评估工具有效性并识别潜在的异常值SNP。P值小于0.05被认为具有统计学意义。
MR分析显示BMI对MS有因果效应，IVW（优势比（OR） = 1.39；95%置信区间（CI） = 1.23，1.58；P = 1.42e-07）、具有修正二阶权重的IVW方法（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-基因型编码不变性属性（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）和GSMR（OR = 1.38；95% CI = 1.23，1.55；P = 3.35e-08）均表明了这一点。未检测到水平多效性或异质性的证据，且研究结果被证实是稳健的。
本研究提供了证据表明体型增加（BMI）可导致MS。因此，在生命早期保持健康体重可能是降低MS风险的潜在策略。
