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

Journal article
Authors D. Manousaki
T. Dudding
S. Haworth
Y. H. Hsu
C. T. Liu
C. Medina-Gomez
T. Voortman
N. van der Velde
H. Melhus
C. Robinson-Cohen
D. L. Cousminer
Maria Nethander
Liesbeth Vandenput
R. Noordam
V. Forgetta
C. M. T. Greenwood
M. L. Biggs
B. M. Psaty
J. I. Rotter
B. S. Zemel
B. Taylor
Mattias Lorentzon
M. Karlsson
V. V. W. Jaddoe
H. Tiemeier
N. Campos-Obando
O. H. Franco
A. G. Utterlinden
L. Broer
N. M. van Schoor
A. C. Ham
M. A. Ikram
D. Karasik
R. de Mutsert
F. R. Rosendaal
M. den Heijer
T. J. Wang
L. Lind
E. S. Orwoll
D. O. Mook-Kanamori
K. Michaelsson
B. Kestenbaum
Claes Ohlsson
Dan Mellström
Lcpgm de Groot
S. F. A. Grant
D. P. Kiel
M. C. Zillikens
F. Rivadeneira
S. Sawcer
N. J. Timpson
J. B. Richards
Journal Of Pediatrics V. P. Sella Sj
Published in American Journal of Human Genetics
Volume 101
Issue 2
Pages 227-238
ISSN 0002-9297
Publication year 2017
Published at Core Facilities, Bioinformatics
Centre for Bone and Arthritis Research
Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Pages 227-238
Language en
Keywords genome-wide association, sequencing data, reference panel, rare, variants, plasma-levels, imputation, discovery, framework, alleles, Genetics & Heredity
Subject categories Basic Medicine


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 x 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 3 10 x(-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 3 10 x(-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.

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