title: Causal Effect of Genetic Variants Associated With Body Mass Index on Multiple Sclerosis Susceptibility.
abstract: Multiple sclerosis (MS) is an autoimmune disease with both genetic and environmental risk factors. Recent studies indicate that childhood and adolescent obesity double the risk of MS, but this association may reflect unmeasured confounders rather than causal effects of obesity. We used separate-sample Mendelian randomization to estimate the causal effect of body mass index (BMI) on susceptibility to MS. Using data from non-Hispanic white members of the Kaiser Permanente Medical Care Plan of Northern California (KPNC) (2006-2014; 1,104 cases of MS and 10,536 controls) and a replication data set from Sweden (the Epidemiological Investigation of MS (EIMS) and the Genes and Environment in MS (GEMS) studies, 2005-2013; 5,133 MS cases and 4,718 controls), we constructed a weighted genetic risk score using 97 variants previously established to predict BMI. Results were adjusted for birth year, sex, education, smoking status, ancestry, and genetic predictors of MS. Estimates in KPNC and Swedish data sets suggested that higher genetically induced BMI predicted greater susceptibility to MS (odds ratio = 1.13, 95% confidence interval: 1.04, 1.22 for the KPNC sample; odds ratio = 1.09, 95% confidence interval: 1.03, 1.15 for the Swedish sample). Although the mechanism remains unclear, to our knowledge, these findings support a causal effect of increased BMI on susceptibility to MS for the first time, and they suggest a role for inflammatory pathways that characterize both obesity and the MS disease process.
authors.affiliation: Genetic Epidemiology and Genomics Lab, Division of Epidemiology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
authors.forename: Milena A
authors.initials: MA
authors.lastname: Gianfrancesco
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, USA.
authors.forename: M Maria
authors.initials: MM
authors.lastname: Glymour
authors.affiliation: Institute of Clinical and Experimental Medicine, Division of Gastroenterology, Linköping University, Linköping, Sweden.|Center for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Walter
authors.affiliation: Computational Biology Graduate Group, University of California, Berkeley, CA, USA.
authors.forename: Brooke
authors.initials: B
authors.lastname: Rhead
authors.affiliation: Centre for Reproductive Medicine, Dalian Maternal and Children's Centre, Dalian, China.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Shao
authors.affiliation: Collaborative Innovation Center on Forecast and Evaluation of Meteorological Disasters, Jiangsu Key Laboratory of Agricultural Meteorology, Department of Agricultural Resource and Environment, College of Applied Meteorology, University of Information Science and Technology, Nanjing, 210044, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Shen
authors.affiliation: Human Evolutionary Genetics, Institut Pasteur, 75015 Paris, France.|Centre National de la Recherche Scientifique URA3012, 75015 Paris, France.|Center of Bioinformatics, Biostatistics, and Integrative Biology, Institut Pasteur, 75015 Paris, France.
authors.forename: Hong
authors.initials: H
authors.lastname: Quach
authors.affiliation: Institute of Pharmaceutical Science, King's College London, London, UK; Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Hubbard
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Department of Immunology, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.|Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Ingileif
authors.initials: I
authors.lastname: Jónsdóttir
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Kári
authors.initials: K
authors.lastname: Stefánsson
authors.forename: Pernilla
authors.initials: P
authors.lastname: Strid
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Hillert
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
authors.forename: Anna
authors.initials: A
authors.lastname: Hedström
authors.affiliation: Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden/Department of Neurology, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kockum
authors.affiliation: Department of Soil Science, Federal University of Viçosa, Viçosa, MG, Brazil.
authors.forename: Catherine
authors.initials: C
authors.lastname: Schaefer
authors.affiliation: Centre for Occupational and Environmental Medicine, Stockholm County Council, Sweden.|Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.affiliation: Division of Epidemiology, School of Public Health, University of California, 324 Stanley Hall, Berkeley, CA, USA.
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Barcellos
mesh_terms: D000328:Adult; D015992:Body Mass Index; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics*
keywords: Mendelian randomization; body mass index; genetic instrumental variables; multiple sclerosis; obesity