Objective: 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: 43 individuals with MS (one from each family) were sequenced looking for rare variants in candidate MS susceptibility genes. On average over 58000 variants were identified in each individual. A rare variant in the CYP27B1 gene causing complete loss of gene function was identified in one individual. Homozygosity (two copies of the gene) for this mutation results in vitamin D dependent rickets I (VDDR1), while heterozygosity (one copy of the gene) results in lower calcitriol or vD levels. This variant showed significant heterozygous association in 3046 parent-affected child trios, P=1×10-5. Further genotyping in over 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 35/35 times (P=3×10-9).
Interpretation: A causative role for CYP27B1 in MS is supported, indeed 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.