title: Rare variants in the CYP27B1 gene are associated with multiple sclerosis.
abstract: OBJECTIVE
  Multiple sclerosis (MS) is a complex neurological disease. Genetic linkage analysis and genotyping of candidate genes in families with 4 or more affected individuals more heavily loaded for susceptibility genes has not fully explained familial disease clustering.
  
  
  METHODS
  We performed whole exome sequencing to further understand the heightened prevalence of MS in these families.
  
  
  RESULTS
  Forty-three individuals with MS (1 from each family) were sequenced to find rare variants in candidate MS susceptibility genes. On average, >58,000 variants were identified in each individual. A rare variant in the CYP27B1 gene causing complete loss of gene function was identified in 1 individual. Homozygosity for this mutation results in vitamin D-dependent rickets I (VDDR1), whereas heterozygosity results in lower calcitriol levels. This variant showed significant heterozygous association in 3,046 parent-affected child trios (p = 1 × 10(-5)). Further genotyping in >12,500 individuals showed that other rare loss of function CYP27B1 variants also conferred significant risk of MS, Peto odds ratio = 4.7 (95% confidence interval, 2.3-9.4; p = 5 × 10(-7)). Four known VDDR1 mutations were identified, all overtransmitted. Heterozygous parents transmitted these alleles to MS offspring 35 of 35× (p = 3 × 10(-9)).
  
  
  CONCLUSIONS
  A causative role for CYP27B1 in MS is supported; the mutations identified are known to alter function having been shown in vivo to result in rickets when 2 copies are present. CYP27B1 encodes the vitamin D-activating 1-alpha hydroxylase enzyme, and thus a role for vitamin D in MS pathogenesis is strongly implicated.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Sreeram V
authors.initials: SV
authors.lastname: Ramagopalan
authors.forename: David A
authors.initials: DA
authors.lastname: Dyment
authors.forename: M Zameel
authors.initials: MZ
authors.lastname: Cader
authors.forename: Katie M
authors.initials: KM
authors.lastname: Morrison
authors.forename: Giulio
authors.initials: G
authors.lastname: Disanto
authors.forename: Julia M
authors.initials: JM
authors.lastname: Morahan
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Berlanga-Taylor
authors.forename: Adam
authors.initials: A
authors.lastname: Handel
authors.forename: Gabriele C
authors.initials: GC
authors.lastname: De Luca
authors.forename: A Dessa
authors.initials: AD
authors.lastname: Sadovnick
authors.forename: Pierre
authors.initials: P
authors.lastname: Lepage
authors.forename: Alexandre
authors.initials: A
authors.lastname: Montpetit
authors.forename: George C
authors.initials: GC
authors.lastname: Ebers
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics*; D017668:Age of Onset; D015331:Cohort Studies; D059472:Exome / Q000235:genetics; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000150:complications / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D014808:Vitamin D Deficiency / Q000150:complications / Q000235:genetics
chemical_list: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase