title: Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk.
abstract: OBJECTIVE
  We sought to estimate the causal effect of low serum 25(OH)D on multiple sclerosis (MS) susceptibility that is not confounded by environmental or lifestyle factors or subject to reverse causality.
  
  
  METHODS
  We conducted mendelian randomization (MR) analyses using an instrumental variable (IV) comprising 3 single nucleotide polymorphisms found to be associated with serum 25(OH)D levels at genome-wide significance. We analyzed the effect of the IV on MS risk and both age at onset and disease severity in 2 separate populations using logistic regression models that controlled for sex, year of birth, smoking, education, genetic ancestry, body mass index at age 18-20 years or in 20s, a weighted genetic risk score for 110 known MS-associated variants, and the presence of one or more HLA-DRB1*15:01 alleles.
  
  
  RESULTS
  Findings from MR analyses using the IV showed increasing levels of 25(OH)D are associated with a decreased risk of MS in both populations. In white, non-Hispanic members of Kaiser Permanente Northern California (1,056 MS cases and 9,015 controls), the odds ratio (OR) was 0.79 (p = 0.04, 95% confidence interval (CI): 0.64-0.99). In members of a Swedish population from the Epidemiological Investigation of Multiple Sclerosis and Genes and Environment in Multiple Sclerosis MS case-control studies (6,335 cases and 5,762 controls), the OR was 0.86 (p = 0.03, 95% CI: 0.76-0.98). A meta-analysis of the 2 populations gave a combined OR of 0.85 (p = 0.003, 95% CI: 0.76-0.94). No association was observed for age at onset or disease severity.
  
  
  CONCLUSIONS
  These results provide strong evidence that low serum 25(OH)D concentration is a cause of MS, independent of established risk factors.
authors.affiliation: Computational Biology Graduate Group (B.R.), Division of Epidemiology (M.G., A.M., X.S., H.Q., L.F.B.), School of Public Health, University of California, Berkeley; Institute of Environmental Medicine (M.B., A.K.H., L.A.), Karolinska Institutet, Stockholm, Sweden; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Research Program on Genes, Environment, and Health (C.S.), Kaiser Permanente, Oakland, CA; Department of Clinical Neuroscience and Center for Molecular Medicine (J.L., A.G., T.O., J.H., I.K.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Epidemiology and Biostatistics (M.M.G.), University of California, San Francisco; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.
authors.forename: Brooke
authors.initials: B
authors.lastname: Rhead
authors.affiliation: Computational Biology Graduate Group (B.R.), Division of Epidemiology (M.G., A.M., X.S., H.Q., L.F.B.), School of Public Health, University of California, Berkeley; Institute of Environmental Medicine (M.B., A.K.H., L.A.), Karolinska Institutet, Stockholm, Sweden; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Research Program on Genes, Environment, and Health (C.S.), Kaiser Permanente, Oakland, CA; Department of Clinical Neuroscience and Center for Molecular Medicine (J.L., A.G., T.O., J.H., I.K.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Epidemiology and Biostatistics (M.M.G.), University of California, San Francisco; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Bäärnhielm
authors.affiliation: Computational Biology Graduate Group (B.R.), Division of Epidemiology (M.G., A.M., X.S., H.Q., L.F.B.), School of Public Health, University of California, Berkeley; Institute of Environmental Medicine (M.B., A.K.H., L.A.), Karolinska Institutet, Stockholm, Sweden; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Research Program on Genes, Environment, and Health (C.S.), Kaiser Permanente, Oakland, CA; Department of Clinical Neuroscience and Center for Molecular Medicine (J.L., A.G., T.O., J.H., I.K.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Epidemiology and Biostatistics (M.M.G.), University of California, San Francisco; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.
authors.forename: Milena
authors.initials: M
authors.lastname: Gianfrancesco
authors.affiliation: Computational Biology Graduate Group (B.R.), Division of Epidemiology (M.G., A.M., X.S., H.Q., L.F.B.), School of Public Health, University of California, Berkeley; Institute of Environmental Medicine (M.B., A.K.H., L.A.), Karolinska Institutet, Stockholm, Sweden; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Research Program on Genes, Environment, and Health (C.S.), Kaiser Permanente, Oakland, CA; Department of Clinical Neuroscience and Center for Molecular Medicine (J.L., A.G., T.O., J.H., I.K.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Epidemiology and Biostatistics (M.M.G.), University of California, San Francisco; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.
authors.forename: Amanda
authors.initials: A
authors.lastname: Mok
authors.affiliation: Computational Biology Graduate Group (B.R.), Division of Epidemiology (M.G., A.M., X.S., H.Q., L.F.B.), School of Public Health, University of California, Berkeley; Institute of Environmental Medicine (M.B., A.K.H., L.A.), Karolinska Institutet, Stockholm, Sweden; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Research Program on Genes, Environment, and Health (C.S.), Kaiser Permanente, Oakland, CA; Department of Clinical Neuroscience and Center for Molecular Medicine (J.L., A.G., T.O., J.H., I.K.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Epidemiology and Biostatistics (M.M.G.), University of California, San Francisco; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Shao
authors.affiliation: Computational Biology Graduate Group (B.R.), Division of Epidemiology (M.G., A.M., X.S., H.Q., L.F.B.), School of Public Health, University of California, Berkeley; Institute of Environmental Medicine (M.B., A.K.H., L.A.), Karolinska Institutet, Stockholm, Sweden; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Research Program on Genes, Environment, and Health (C.S.), Kaiser Permanente, Oakland, CA; Department of Clinical Neuroscience and Center for Molecular Medicine (J.L., A.G., T.O., J.H., I.K.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Epidemiology and Biostatistics (M.M.G.), University of California, San Francisco; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.
authors.forename: Hong
authors.initials: H
authors.lastname: Quach
authors.affiliation: Computational Biology Graduate Group (B.R.), Division of Epidemiology (M.G., A.M., X.S., H.Q., L.F.B.), School of Public Health, University of California, Berkeley; Institute of Environmental Medicine (M.B., A.K.H., L.A.), Karolinska Institutet, Stockholm, Sweden; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Research Program on Genes, Environment, and Health (C.S.), Kaiser Permanente, Oakland, CA; Department of Clinical Neuroscience and Center for Molecular Medicine (J.L., A.G., T.O., J.H., I.K.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Epidemiology and Biostatistics (M.M.G.), University of California, San Francisco; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.
authors.forename: Ling
authors.initials: L
authors.lastname: Shen
authors.affiliation: Computational Biology Graduate Group (B.R.), Division of Epidemiology (M.G., A.M., X.S., H.Q., L.F.B.), School of Public Health, University of California, Berkeley; Institute of Environmental Medicine (M.B., A.K.H., L.A.), Karolinska Institutet, Stockholm, Sweden; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Research Program on Genes, Environment, and Health (C.S.), Kaiser Permanente, Oakland, CA; Department of Clinical Neuroscience and Center for Molecular Medicine (J.L., A.G., T.O., J.H., I.K.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Epidemiology and Biostatistics (M.M.G.), University of California, San Francisco; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.
authors.forename: Catherine
authors.initials: C
authors.lastname: Schaefer
authors.affiliation: Computational Biology Graduate Group (B.R.), Division of Epidemiology (M.G., A.M., X.S., H.Q., L.F.B.), School of Public Health, University of California, Berkeley; Institute of Environmental Medicine (M.B., A.K.H., L.A.), Karolinska Institutet, Stockholm, Sweden; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Research Program on Genes, Environment, and Health (C.S.), Kaiser Permanente, Oakland, CA; Department of Clinical Neuroscience and Center for Molecular Medicine (J.L., A.G., T.O., J.H., I.K.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Epidemiology and Biostatistics (M.M.G.), University of California, San Francisco; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Link
authors.affiliation: Computational Biology Graduate Group (B.R.), Division of Epidemiology (M.G., A.M., X.S., H.Q., L.F.B.), School of Public Health, University of California, Berkeley; Institute of Environmental Medicine (M.B., A.K.H., L.A.), Karolinska Institutet, Stockholm, Sweden; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Research Program on Genes, Environment, and Health (C.S.), Kaiser Permanente, Oakland, CA; Department of Clinical Neuroscience and Center for Molecular Medicine (J.L., A.G., T.O., J.H., I.K.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Epidemiology and Biostatistics (M.M.G.), University of California, San Francisco; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gyllenberg
authors.affiliation: Computational Biology Graduate Group (B.R.), Division of Epidemiology (M.G., A.M., X.S., H.Q., L.F.B.), School of Public Health, University of California, Berkeley; Institute of Environmental Medicine (M.B., A.K.H., L.A.), Karolinska Institutet, Stockholm, Sweden; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Research Program on Genes, Environment, and Health (C.S.), Kaiser Permanente, Oakland, CA; Department of Clinical Neuroscience and Center for Molecular Medicine (J.L., A.G., T.O., J.H., I.K.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Epidemiology and Biostatistics (M.M.G.), University of California, San Francisco; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.
authors.forename: Anna Karin
authors.initials: AK
authors.lastname: Hedström
authors.affiliation: Computational Biology Graduate Group (B.R.), Division of Epidemiology (M.G., A.M., X.S., H.Q., L.F.B.), School of Public Health, University of California, Berkeley; Institute of Environmental Medicine (M.B., A.K.H., L.A.), Karolinska Institutet, Stockholm, Sweden; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Research Program on Genes, Environment, and Health (C.S.), Kaiser Permanente, Oakland, CA; Department of Clinical Neuroscience and Center for Molecular Medicine (J.L., A.G., T.O., J.H., I.K.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Epidemiology and Biostatistics (M.M.G.), University of California, San Francisco; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.affiliation: Computational Biology Graduate Group (B.R.), Division of Epidemiology (M.G., A.M., X.S., H.Q., L.F.B.), School of Public Health, University of California, Berkeley; Institute of Environmental Medicine (M.B., A.K.H., L.A.), Karolinska Institutet, Stockholm, Sweden; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Research Program on Genes, Environment, and Health (C.S.), Kaiser Permanente, Oakland, CA; Department of Clinical Neuroscience and Center for Molecular Medicine (J.L., A.G., T.O., J.H., I.K.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Epidemiology and Biostatistics (M.M.G.), University of California, San Francisco; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Hillert
authors.affiliation: Computational Biology Graduate Group (B.R.), Division of Epidemiology (M.G., A.M., X.S., H.Q., L.F.B.), School of Public Health, University of California, Berkeley; Institute of Environmental Medicine (M.B., A.K.H., L.A.), Karolinska Institutet, Stockholm, Sweden; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Research Program on Genes, Environment, and Health (C.S.), Kaiser Permanente, Oakland, CA; Department of Clinical Neuroscience and Center for Molecular Medicine (J.L., A.G., T.O., J.H., I.K.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Epidemiology and Biostatistics (M.M.G.), University of California, San Francisco; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kockum
authors.affiliation: Computational Biology Graduate Group (B.R.), Division of Epidemiology (M.G., A.M., X.S., H.Q., L.F.B.), School of Public Health, University of California, Berkeley; Institute of Environmental Medicine (M.B., A.K.H., L.A.), Karolinska Institutet, Stockholm, Sweden; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Research Program on Genes, Environment, and Health (C.S.), Kaiser Permanente, Oakland, CA; Department of Clinical Neuroscience and Center for Molecular Medicine (J.L., A.G., T.O., J.H., I.K.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Epidemiology and Biostatistics (M.M.G.), University of California, San Francisco; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.
authors.forename: M Maria
authors.initials: MM
authors.lastname: Glymour
authors.affiliation: Computational Biology Graduate Group (B.R.), Division of Epidemiology (M.G., A.M., X.S., H.Q., L.F.B.), School of Public Health, University of California, Berkeley; Institute of Environmental Medicine (M.B., A.K.H., L.A.), Karolinska Institutet, Stockholm, Sweden; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Research Program on Genes, Environment, and Health (C.S.), Kaiser Permanente, Oakland, CA; Department of Clinical Neuroscience and Center for Molecular Medicine (J.L., A.G., T.O., J.H., I.K.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Epidemiology and Biostatistics (M.M.G.), University of California, San Francisco; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.affiliation: Computational Biology Graduate Group (B.R.), Division of Epidemiology (M.G., A.M., X.S., H.Q., L.F.B.), School of Public Health, University of California, Berkeley; Institute of Environmental Medicine (M.B., A.K.H., L.A.), Karolinska Institutet, Stockholm, Sweden; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Research Program on Genes, Environment, and Health (C.S.), Kaiser Permanente, Oakland, CA; Department of Clinical Neuroscience and Center for Molecular Medicine (J.L., A.G., T.O., J.H., I.K.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Epidemiology and Biostatistics (M.M.G.), University of California, San Francisco; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Barcellos