Childhood obesity and multiple sclerosis: A Mendelian randomization study.
Adil Harroud, Ruth E Mitchell, Tom G Richardson, John A Morris, Vincenzo Forgetta, George Davey Smith, Sergio E Baranzini, J Brent Richards
Author Information
Adil Harroud: Department of Neurology, University of California San Francisco, San Francisco, CA, USA/Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA/Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada. ORCID
Ruth E Mitchell: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK/Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Tom G Richardson: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK/Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
John A Morris: New York Genome Center and Department of Biology, New York University, New York City, NY, USA.
Vincenzo Forgetta: Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada/Department of Human Genetics, McGill University, Montreal, QC, Canada.
George Davey Smith: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK/Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Sergio E Baranzini: Department of Neurology, University of California San Francisco, San Francisco, CA, USA/Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA/Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA/Bakar Computational Health Sciences Institute, University of California San Francisco, San Francisco, CA, USA. ORCID
J Brent Richards: Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada/Department of Human Genetics, McGill University, Montreal, QC, Canada/Department of Medicine, McGill University Montreal, QC, Canada/Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada/Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.
BACKGROUND: Higher childhood body mass index (BMI) has been associated with an increased risk of multiple sclerosis (MS). OBJECTIVE: To evaluate whether childhood BMI has a causal influence on MS, and whether this putative effect is independent from early adult obesity and pubertal timing. METHODS: We performed Mendelian randomization (MR) using summary genetic data on 14,802 MS cases and 26,703 controls. Large-scale genome-wide association studies provided estimates for BMI in childhood ( = 47,541) and adulthood ( = 322,154). In multivariable MR, we examined the direct effects of each timepoint and further adjusted for age at puberty. Findings were replicated using the UK Biobank ( = 453,169). RESULTS: Higher genetically predicted childhood BMI was associated with increased odds of MS (odds ratio (OR) = 1.26/SD BMI increase, 95% confidence interval (CI): 1.07-1.50). However, there was little evidence of a direct effect after adjusting for adult BMI (OR = 1.03, 95% CI: 0.70-1.53). Conversely, the effect of adult BMI persisted independent of childhood BMI (OR = 1.43; 95% CI: 1.01-2.03). The addition of age at puberty did not alter the findings. UK Biobank analyses showed consistent results. Sensitivity analyses provided no evidence of pleiotropy. CONCLUSION: Genetic evidence supports an association between childhood obesity and MS susceptibility, mediated by persistence of obesity into early adulthood but independent of pubertal timing.
