e-Article
Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis.
Document Type
article
Author
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
Source
American Journal of Human Genetics. 101(2)
Subject
Language
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 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.