- Manousaki, Despoina;
- Dudding, Tom;
- Haworth, Simon;
- Hsu, Yi-Hsiang;
- Liu, Ching-Ti;
- Medina-Gómez, Carolina;
- Voortman, Trudy;
- van der Velde, Nathalie;
- Melhus, Håkan;
- Robinson-Cohen, Cassianne;
- Cousminer, Diana;
- Nethander, Maria;
- Vandenput, Liesbeth;
- Noordam, Raymond;
- Forgetta, Vincenzo;
- Greenwood, Celia;
- Biggs, Mary;
- Psaty, Bruce;
- Zemel, Babette;
- Mitchell, Jonathan;
- Taylor, Bruce;
- Lorentzon, Mattias;
- Karlsson, Magnus;
- Jaddoe, Vincent;
- Tiemeier, Henning;
- Campos-Obando, Natalia;
- Franco, Oscar;
- Utterlinden, Andre;
- Broer, Linda;
- van Schoor, Natasja;
- Ham, Annelies;
- Ikram, M;
- Karasik, David;
- de Mutsert, Renée;
- Rosendaal, Frits;
- den Heijer, Martin;
- Wang, Thomas;
- Lind, Lars;
- Orwoll, Eric;
- Mook-Kanamori, Dennis;
- Michaëlsson, Karl;
- Kestenbaum, Bryan;
- Ohlsson, Claes;
- Mellström, Dan;
- de Groot, Lisette;
- Grant, Struan;
- Kiel, Douglas;
- Zillikens, M;
- Rivadeneira, Fernando;
- Sawcer, Stephen;
- Timpson, Nicholas;
- Richards, J;
- Rotter, Jerome
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.