Rare variants in the CYP27B1 gene are associated with multiple sclerosis

Authors

  • Sreeram V. Ramagopalan DPhil,

    1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    2. Nuffield Department of Clinical Neurosciences (Clinical Neurology), University of Oxford, Oxford, United Kingdom
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  • David A. Dyment MD, DPhil,

    1. Department of Medical Genetics, University of Ottawa, Ottawa, Ontario, Canada
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  • M. Zameel Cader MD, DPhil,

    1. Nuffield Department of Clinical Neurosciences (Clinical Neurology), University of Oxford, Oxford, United Kingdom
    2. Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom
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  • Katie M. Morrison MSc,

    1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    2. Nuffield Department of Clinical Neurosciences (Clinical Neurology), University of Oxford, Oxford, United Kingdom
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  • Giulio Disanto MD,

    1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    2. Nuffield Department of Clinical Neurosciences (Clinical Neurology), University of Oxford, Oxford, United Kingdom
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  • Julia M. Morahan PhD,

    1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    2. Nuffield Department of Clinical Neurosciences (Clinical Neurology), University of Oxford, Oxford, United Kingdom
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  • Antonio J. Berlanga-Taylor MD,

    1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    2. Nuffield Department of Clinical Neurosciences (Clinical Neurology), University of Oxford, Oxford, United Kingdom
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  • Adam Handel MD,

    1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    2. Nuffield Department of Clinical Neurosciences (Clinical Neurology), University of Oxford, Oxford, United Kingdom
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  • Gabriele C. De Luca MD, DPhil,

    1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    2. Nuffield Department of Clinical Neurosciences (Clinical Neurology), University of Oxford, Oxford, United Kingdom
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  • A. Dessa Sadovnick PhD,

    1. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
    2. Faculty of Medicine, Division of Neurology, University of British Columbia, Vancouver, British Columbia, Canada
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  • Pierre Lepage PhD,

    1. McGill University and Genome Québec Innovation Centre, Montreal, Quebec, Canada
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  • Alexandre Montpetit PhD,

    1. McGill University and Genome Québec Innovation Centre, Montreal, Quebec, Canada
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  • George C. Ebers MD, FRCP, FMedSci

    Corresponding author
    1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    2. Nuffield Department of Clinical Neurosciences (Clinical Neurology), University of Oxford, Oxford, United Kingdom
    • Nuffield Department of Clinical Neurosciences (Clinical Neurology), Level 3, West Wing, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom
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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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