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

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.

• Authors: Despoina Manousaki, Tom Dudding, Simon Haworth, Yi-Hsiang Hsu, Ching-Ti Liu, Carolina Medina-Gómez, Trudy Voortman, Nathalie van der Velde, Håkan Melhus, Cassianne Robinson-Cohen, Diana L Cousminer, Maria Nethander, Liesbeth Vandenput, Raymond Noordam, Vincenzo Forgetta, Celia M T Greenwood, Mary L Biggs, Bruce M Psaty, Jerome I Rotter, Babette S Zemel, Jonathan A Mitchell, Bruce Taylor, Mattias Lorentzon, Magnus Karlsson, Vincent V W Jaddoe, Henning Tiemeier, Natalia Campos-Obando, Oscar H Franco, Andre G Utterlinden, Linda Broer, Natasja M van Schoor, Annelies C Ham, M Arfan Ikram, David Karasik, Renée de Mutsert, Frits R Rosendaal, Martin den Heijer, Thomas J Wang, Lars Lind, Eric S Orwoll, Dennis O Mook-Kanamori, Karl Michaëlsson, Bryan Kestenbaum, Claes Ohlsson, Dan Mellström, Lisette C P G M de Groot, Struan F A Grant, Douglas P Kiel, M Carola Zillikens, Fernando Rivadeneira, Stephen Sawcer, Nicholas J Timpson, J Brent Richards
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 101 Issue 2 Pg. 227-238 (Aug 03 2017) ISSN: 1537-6605 [Electronic] United States
• PMID: 28757204 (Publication Type: Journal Article, Meta-Analysis)
• Copyright: Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Vitamin D
• 25-hydroxyvitamin D
• Cytochrome P450 Family 2
• CYP2R1 protein, human
• Cholestanetriol 26-Monooxygenase

Topics

• Cholestanetriol 26-Monooxygenase (genetics)
• Cytochrome P450 Family 2 (genetics)
• Gene Frequency
• Genetic Predisposition to Disease (genetics)
• Genome, Human (genetics)
• Genome-Wide Association Study
• Humans
• Multiple Sclerosis (etiology, genetics)
• Polymorphism, Single Nucleotide
• Risk Factors
• Vitamin D (analogs & derivatives, blood)
• Vitamin D Deficiency (diagnosis, genetics)