Rare variants in the CYP27B1 gene are associated with multiple sclerosis
Version of Record online: 21 DEC 2011
Copyright © 2011 American Neurological Association
Annals of Neurology
Volume 70, Issue 6, pages 881–886, December 2011
How to Cite
Ramagopalan, S. V., Dyment, D. A., Cader, M. Z., Morrison, K. M., Disanto, G., Morahan, J. M., Berlanga-Taylor, A. J., Handel, A., De Luca, G. C., Sadovnick, A. D., Lepage, P., Montpetit, A. and Ebers, G. C. (2011), Rare variants in the CYP27B1 gene are associated with multiple sclerosis. Ann Neurol., 70: 881–886. doi: 10.1002/ana.22678
- Issue online: 21 DEC 2011
- Version of Record online: 21 DEC 2011
- Accepted manuscript online: 25 NOV 2011 08:36AM EST
- Manuscript Accepted: 15 NOV 2011
- Manuscript Received: 4 NOV 2011
- Manuscript Revised: 4 NOV 2011
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.
We performed whole exome sequencing to further understand the heightened prevalence of MS in these families.
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).
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