title: Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study.
abstract: BACKGROUND
  Observational studies have demonstrated an association between decreased vitamin D level and risk of multiple sclerosis (MS); however, it remains unclear whether this relationship is causal. We undertook a Mendelian randomization (MR) study to evaluate whether genetically lowered vitamin D level influences the risk of MS.
  
  
  RESULTS
  We identified single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D (25OHD) level from SUNLIGHT, the largest (n = 33,996) genome-wide association study to date for vitamin D. Four SNPs were genome-wide significant for 25OHD level (p-values ranging from 6 × 10-10 to 2 × 10-109), and all four SNPs lay in, or near, genes strongly implicated in separate mechanisms influencing 25OHD. We then ascertained their effect on 25OHD level in 2,347 participants from a population-based cohort, the Canadian Multicentre Osteoporosis Study, and tested the extent to which the 25OHD-decreasing alleles explained variation in 25OHD level. We found that the count of 25OHD-decreasing alleles across these four SNPs was strongly associated with lower 25OHD level (n = 2,347, F-test statistic = 49.7, p = 2.4 × 10-12). Next, we conducted an MR study to describe the effect of genetically lowered 25OHD on the odds of MS in the International Multiple Sclerosis Genetics Consortium study, the largest genetic association study to date for MS (including up to 14,498 cases and 24,091 healthy controls). Alleles were weighted by their relative effect on 25OHD level, and sensitivity analyses were performed to test MR assumptions. MR analyses found that each genetically determined one-standard-deviation decrease in log-transformed 25OHD level conferred a 2.0-fold increase in the odds of MS (95% CI: 1.7-2.5; p = 7.7 × 10-12; I2 = 63%, 95% CI: 0%-88%). This result persisted in sensitivity analyses excluding SNPs possibly influenced by population stratification or pleiotropy (odds ratio [OR] = 1.7, 95% CI: 1.3-2.2; p = 2.3 × 10-5; I2 = 47%, 95% CI: 0%-85%) and including only SNPs involved in 25OHD synthesis or metabolism (ORsynthesis = 2.1, 95% CI: 1.6-2.6, p = 1 × 10-9; ORmetabolism = 1.9, 95% CI: 1.3-2.7, p = 0.002). While these sensitivity analyses decreased the possibility that pleiotropy may have biased the results, residual pleiotropy is difficult to exclude entirely.
  
  
  CONCLUSIONS
  A genetically lowered 25OHD level is strongly associated with increased susceptibility to MS. Whether vitamin D sufficiency can delay, or prevent, MS onset merits further investigation in long-term randomized controlled trials.
authors: Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors: Lauren E
authors: LE
authors: Mokry
authors: Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors: Stephanie
authors: S
authors: Ross
authors: 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.
authors: Omar S
authors: OS
authors: Ahmad
authors: 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.
authors: Vincenzo
authors: V
authors: Forgetta
authors: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors: George Davey
authors: GD
authors: Smith
authors: Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors: David
authors: D
authors: Goltzman
authors: Division of General Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Aaron
authors: A
authors: Leong
authors: Department of Oncology, McGill University, Montreal, Quebec, Canada; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.
authors: Celia M T
authors: CM
authors: Greenwood
authors: Department of Medicine, McGill University, Montreal, Quebec, Canada; Preventive and Genomic Cardiology, McGill University Health Center, Montreal, QC.
authors: George
authors: G
authors: Thanassoulis
authors: 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 Epidemiology, Biostatistics and Occupational Health, 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, United Kingdom.
authors: J Brent
authors: JB
authors: Richards
mesh_terms: D005060:Europe; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D057182:Mendelian Randomization Analysis; D009103:Multiple Sclerosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors; D014808:Vitamin D Deficiency / Q000235:genetics*