Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis

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 (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10-88). 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 (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10-12). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10-5) 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.

Bibliographic Details

Main Authors:	Manousaki, Despoina, Dudding, Tom, Haworth, Simon, Hsu, Yi Hsiang, Liu, Ching Ti, Medina-Gómez, Carolina, Voortman, Trudy, Van Der Velde, Nathalie, Melhus, Håkan, Vandenput, Liesbeth, Noordam, Raymond, Forgetta, Vincenzo, Greenwood, Celia M.T., Biggs, Mary L., Psaty, Bruce M., Rotter, Jerome I., Zemel, Babette S., Mitchell, Jonathan A., Taylor, Bruce, Lorentzon, Mattias, Karlsson, Magnus, Jaddoe, Vincent W.V., Tiemeier, Henning, Campos-Obando, Natalia, Franco, Oscar H., Utterlinden, Andre G., Broer, Linda, van Schoor, Natasja M., Ham, Annelies C., Ikram, Arfan M.A., Karasik, David, De Mutsert, Renée, Rosendaal, Frits R., den Heijer, Martin, Wang, Thomas J., Lind, Lars, Orwoll, Eric S., Mook-Kanamori, Dennis O., Michaëlsson, Karl, Kestenbaum, Bryan, Ohlsson, Claes, Mellström, Dan, de Groot, Lisette C.P.G.M., Grant, Struan F.A., Kiel, Douglas P., Zillikens, M.C., Rivadeneira, Fernando, Sawcer, Stephen, Timpson, Nicholas J., Richards, J.B.
Format:	Article/Letter to editor biblioteca
Language:	English
Subjects:	GWAS, Low-frequency genetic variants, Multiple sclerosis, Vitamin D,
Online Access:	https://research.wur.nl/en/publications/low-frequency-synonymous-coding-variation-in-cyp2r1-has-large-eff
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