Rare variants in the CYP27B1 gene are associated with multiple sclerosis

Ann Neurol. 2011 Dec;70(6):881-6. doi: 10.1002/ana.22678.


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)).

Interpretation: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / genetics*
  • Age of Onset
  • Cohort Studies
  • Exome / genetics
  • Family Health
  • Female
  • Gene Frequency
  • Genetic Association Studies
  • Genetic Linkage
  • Genetic Predisposition to Disease*
  • Genotype
  • Humans
  • Male
  • Multiple Sclerosis / complications
  • Multiple Sclerosis / genetics*
  • Mutation / genetics*
  • Vitamin D Deficiency / complications
  • Vitamin D Deficiency / genetics


  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase