TY - JOUR T1 - Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis. JF - Am J Hum Genet Y1 - 2017 A1 - Manousaki, Despoina A1 - Dudding, Tom A1 - Haworth, Simon A1 - Hsu, Yi-Hsiang A1 - Liu, Ching-Ti A1 - Medina-Gómez, Carolina A1 - Voortman, Trudy A1 - van der Velde, Nathalie A1 - Melhus, Håkan A1 - Robinson-Cohen, Cassianne A1 - Cousminer, Diana L A1 - Nethander, Maria A1 - Vandenput, Liesbeth A1 - Noordam, Raymond A1 - Forgetta, Vincenzo A1 - Greenwood, Celia M T A1 - Biggs, Mary L A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Zemel, Babette S A1 - Mitchell, Jonathan A A1 - Taylor, Bruce A1 - Lorentzon, Mattias A1 - Karlsson, Magnus A1 - Jaddoe, Vincent V W A1 - Tiemeier, Henning A1 - Campos-Obando, Natalia A1 - Franco, Oscar H A1 - Utterlinden, Andre G A1 - Broer, Linda A1 - van Schoor, Natasja M A1 - Ham, Annelies C A1 - Ikram, M Arfan A1 - Karasik, David A1 - de Mutsert, Renée A1 - Rosendaal, Frits R A1 - den Heijer, Martin A1 - Wang, Thomas J A1 - Lind, Lars A1 - Orwoll, Eric S A1 - Mook-Kanamori, Dennis O A1 - Michaëlsson, Karl A1 - Kestenbaum, Bryan A1 - Ohlsson, Claes A1 - Mellström, Dan A1 - de Groot, Lisette C P G M A1 - Grant, Struan F A A1 - Kiel, Douglas P A1 - Zillikens, M Carola A1 - Rivadeneira, Fernando A1 - Sawcer, Stephen A1 - Timpson, Nicholas J A1 - Richards, J Brent KW - Cholestanetriol 26-Monooxygenase KW - Cytochrome P450 Family 2 KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Multiple Sclerosis KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Vitamin D KW - Vitamin D Deficiency AB -

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.

VL - 101 IS - 2 ER -