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Rare variants in the CYP27B1 gene are associated with multiple sclerosis
- Source :
- Annals of neurology. 70(6)
- Publication Year :
- 2011
-
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
- Subjects :
- Male
Candidate gene
Multiple Sclerosis
Genotype
Genetic Linkage
Single-nucleotide polymorphism
Biology
Cohort Studies
Loss of heterozygosity
Gene Frequency
Genetic linkage
Genetic variation
Humans
Exome
Genetic Predisposition to Disease
Age of Onset
Genotyping
Genetic Association Studies
Exome sequencing
25-Hydroxyvitamin D3 1-alpha-Hydroxylase
Family Health
Genetics
Haplotype
Vitamin D Deficiency
Neurology
Mutation
Female
Neurology (clinical)
Subjects
Details
- Language :
- English
- ISSN :
- 15318249 and 03645134
- Volume :
- 70
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Annals of neurology
- Accession number :
- edsair.doi.dedup.....ab79822330d087b1216a9409066e2f3b