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

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. ZemelJonathan 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

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)227-238
Number of pages12
JournalAmerican Journal of Human Genetics
Volume101
Issue number2
DOIs
StatePublished - Aug 3 2017

Keywords

  • GWAS
  • low-frequency genetic variants
  • multiple sclerosis
  • vitamin D

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis'. Together they form a unique fingerprint.

Cite this