title: Obesity and Multiple Sclerosis: A Mendelian Randomization Study.
abstract: Observational 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.
  
  
  
  Employing 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.
  
  
  
  Genetically 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.
authors.affiliation: Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada.|Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Mokry
authors.affiliation: Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ross
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Nicholas J
authors.identifier: 0000-0002-7141-9189
authors.initials: NJ
authors.lastname: Timpson
authors.affiliation: Department of Clinical Neurosciences, Cambridge Biomedical Campus, Cambridge, United Kingdom.
authors.forename: Stephen
authors.identifier: 0000-0001-7685-0974
authors.initials: S
authors.lastname: Sawcer
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada.|Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.|Department of Medicine, McGill University, Montreal, Quebec, Canada.|Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
authors.forename: J Brent
authors.initials: JB
authors.lastname: Richards
mesh_terms: D015992:Body Mass Index; D055106:Genome-Wide Association Study; D006801:Humans; D057182:Mendelian Randomization Analysis; D009103:Multiple Sclerosis / Q000209:etiology*; D009765:Obesity / Q000150:complications* / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide