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 increase 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 individuals genotyped genome-wide.
Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency synonymous coding variant g.14900931G>A, which conferred a large effect on 25-hydroxyvitamin D levels. 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. Individuals carrying one copy of this variant also had increased odds of multiple sclerosis in a sample of 5,927 case and 5,599 control subjects.
In conclusion, we describe a low-frequency CYP2R1 coding variant that 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 GWAS, low-frequency genetic variants, multiple sclerosis, vitamin D
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Journal American Journal of Human Genetics
Manousaki, D, Dudding, T, Haworth, S, Hsu, Y.-H, Liu, C.-T, Medina-Gomez, M.C, … Richards, J.B. (2017). Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis. American Journal of Human Genetics, 101(2), 227–238. doi:10.1016/j.ajhg.2017.06.014