Obesity and Multiple Sclerosis: A Mendelian Randomization Study.

Lauren E Mokry,J Brent Richards,George Davey Smith,Stephen Sawcer,Nicholas J Timpson,Stephanie Ross,Paolo Antonio Muraro

doi:10.1371/journal.pmed.1002053

Abstract

BackgroundObservational studies have reported an association between obesity, as measured by elevated body mass index (BMI), in early adulthood and risk of multiple sclerosis (MS). However, bias potentially introduced by confounding and reverse causation may have influenced these findings. Therefore, we elected to perform Mendelian randomization (MR) analyses to evaluate whether genetically increased BMI is associated with an increased risk of MS.Methods and FindingsEmploying a two-sample MR approach, we used summary statistics from the Genetic Investigation of Anthropometric Traits (GIANT) consortium and the International MS Genetics Consortium (IMSGC), the largest genome-wide association studies for BMI and MS, respectively (GIANT: n = 322,105; IMSGC: n = 14,498 cases and 24,091 controls). Seventy single nucleotide polymorphisms (SNPs) were genome-wide significant (p < 5 x 10−8) for BMI in GIANT (n = 322,105) and were investigated for their association with MS risk in the IMSGC. The effect of each SNP on MS was weighted by its effect on BMI, and estimates were pooled to provide a summary measure for the effect of increased BMI upon risk of MS. Our results suggest that increased BMI influences MS susceptibility, where a 1 standard deviation increase in genetically determined BMI (kg/m2) increased odds of MS by 41% (odds ratio [OR]: 1.41, 95% CI 1.20–1.66, p = 2.7 x 10−5, I2 = 0%, 95% CI 0–29). Sensitivity analyses, including MR-Egger regression, and the weighted median approach provided no evidence of pleiotropic effects. The main study limitations are that, while these sensitivity analyses reduce the possibility that pleiotropy influenced our results, residual pleiotropy is difficult to exclude entirely.ConclusionGenetically elevated BMI is associated with risk of MS, providing evidence for a causal role for obesity in MS etiology. While obesity has been associated with many late-life outcomes, these findings suggest an important consequence of childhood and/or early adulthood obesity.

Highlights

Multiple sclerosis (MS) is a debilitating autoimmune disease of the central nervous system that results in chronic disability for the majority of those affected [1]
Elevated body mass index (BMI) is associated with risk of MS, providing evidence for a causal role for obesity in MS etiology
While obesity has been associated with many late-life outcomes, these findings suggest an important consequence of childhood and/or early adulthood obesity

Summary

Introduction

Multiple sclerosis (MS) is a debilitating autoimmune disease of the central nervous system that results in chronic disability for the majority of those affected [1]. Elevated BMI has been shown to affect the immune system by promoting a proinflammatory state [7,8,9,10], and it has been proposed that adipose-derived hormones, such as leptin [11] and adiponectin [12], might mediate this, providing a possible mechanistic link between obesity and risk of MS It remains uncertain whether this relationship is causal since it is difficult to fully protect observational studies from bias due to reverse causation or confounding. Mendelian randomization (MR) [13] offers a way to investigate potentially causal relationships by using genetic associations to explore the effect of modifiable exposures on outcomes Since alleles are both independently segregated and randomly assigned at meiosis, bias inherent to observational study designs, such as confounding, is likely to be greatly minimized in MR studies (Fig 1). We elected to perform Mendelian randomization (MR) analyses to evaluate whether genetically increased BMI is associated with an increased risk of MS

Methods

Results

Conclusion