Rare variants in the CYP27B1 gene are associated with multiple sclerosis

✍ Scribed by Sreeram V. Ramagopalan; David A. Dyment; M. Zameel Cader; Katie M. Morrison; Giulio Disanto; Julia M. Morahan; Antonio J. Berlanga-Taylor; Adam Handel; Gabriele C. De Luca; A. Dessa Sadovnick; Pierre Lepage; Alexandre Montpetit; George C. Ebers

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 125 KB
• Volume: 70
• Category: Article
• ISSN: 0364-5134
• DOI: 10.1002/ana.22678

✦ Synopsis

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^).

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. ANN NEUROL 2011;70:881–886