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Rare variants in the CYP27B1 gene are associated with multiple sclerosis

  1. Sreeram V. Ramagopalan DPhil1,2,
  2. David A. Dyment MD, DPhil3,
  3. M. Zameel Cader MD, DPhil2,4,
  4. Katie M. Morrison MSc1,2,
  5. Giulio Disanto MD1,2,
  6. Julia M. Morahan PhD1,2,
  7. Antonio J. Berlanga-Taylor MD1,2,
  8. Adam Handel MD1,2,
  9. Gabriele C. De Luca MD, DPhil1,2,
  10. A. Dessa Sadovnick PhD5,6,
  11. Pierre Lepage PhD7,
  12. Alexandre Montpetit PhD7,
  13. George C. Ebers MD, FRCP, FMedSci1,2,*

Article first published online: 21 DEC 2011

DOI: 10.1002/ana.22678

Issue

Annals of Neurology

Annals of Neurology

Volume 70, Issue 6, pages 881–886, December 2011

Additional Information

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

Author Information

  1. 1

    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom

  2. 2

    Nuffield Department of Clinical Neurosciences (Clinical Neurology), University of Oxford, Oxford, United Kingdom

  3. 3

    Department of Medical Genetics, University of Ottawa, Ottawa, Ontario, Canada

  4. 4

    Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom

  5. 5

    Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada

  6. 6

    Faculty of Medicine, Division of Neurology, University of British Columbia, Vancouver, British Columbia, Canada

  7. 7

    McGill University and Genome Québec Innovation Centre, Montreal, Quebec, Canada

*Nuffield Department of Clinical Neurosciences (Clinical Neurology), Level 3, West Wing, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom

Publication History

  1. Issue published online: 21 DEC 2011
  2. Article first published online: 21 DEC 2011
  3. Accepted manuscript online: 25 NOV 2011 08:36AM EST
  4. Manuscript Accepted: 15 NOV 2011
  5. Manuscript Received: 4 NOV 2011
  6. Manuscript Revised: 4 NOV 2011

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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

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