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Low Frequency Synonymous Coding Variation in CYP2R1 has Large Effects on Vitamin D Level and Risk of Multiple Sclerosis

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Peer-reviewed

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Article

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Authors

Sawcer, SJ 

Abstract

Vitamin D insufficiency is common, correctable and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increased the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep imputation data from 39,655 genome-wide genotyped individuals. Meta-analysis of the summary statistics from 19 cohorts identified a low-frequency synonymous coding p.Asp120Asp variant (rs117913124[A], minor allele frequency=2.5%) in CYP2R1 which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 standard deviations of standardized natural log-transformed 25OHD, per A allele, P-value = 1.5 x10-88). The effect on 25OHD was four-times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (OR=2.2, 95% CI 1.78-2.78, P=1.26 x 10-12). Individuals carrying one copy of this variant had also an increased odds of multiple sclerosis (OR=1.4, 95%CI 1.19-1.64, P=2.63 x 10-5) in a sample of 5,927 cases and 5,599 controls. In conclusion, we describe a low-frequency coding variant in CYP2R1, which exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.

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Keywords

vitamin D, multiple sclerosis, GWAS, low-frequency genetic variants

Journal Title

American Journal of Human Genetics

Conference Name

Journal ISSN

0002-9297
1537-6605

Volume Title

101

Publisher

University of Chicago Press