TY - JOUR
T1 - Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis
AU - Manousaki, Despoina
AU - Dudding, Tom
AU - Haworth, Simon
AU - Hsu, Yi Hsiang
AU - Liu, Ching Ti
AU - Medina-Gómez, Carolina
AU - Voortman, Trudy
AU - van der Velde, Nathalie
AU - Melhus, Håkan
AU - Robinson-Cohen, Cassianne
AU - Cousminer, Diana L.
AU - Nethander, Maria
AU - Vandenput, Liesbeth
AU - Noordam, Raymond
AU - Forgetta, Vincenzo
AU - Greenwood, Celia M.T.
AU - Biggs, Mary L.
AU - Psaty, Bruce M.
AU - Rotter, Jerome I.
AU - Zemel, Babette S.
AU - Mitchell, Jonathan A.
AU - Taylor, Bruce
AU - Lorentzon, Mattias
AU - Karlsson, Magnus
AU - Jaddoe, Vincent V.W.
AU - Tiemeier, Henning
AU - Campos-Obando, Natalia
AU - Franco, Oscar H.
AU - Utterlinden, Andre G.
AU - Broer, Linda
AU - van Schoor, Natasja M.
AU - Ham, Annelies C.
AU - Ikram, M. Arfan
AU - Karasik, David
AU - de Mutsert, Renée
AU - Rosendaal, Frits R.
AU - den Heijer, Martin
AU - Wang, Thomas J.
AU - Lind, Lars
AU - Orwoll, Eric S.
AU - Mook-Kanamori, Dennis O.
AU - Michaëlsson, Karl
AU - Kestenbaum, Bryan
AU - Ohlsson, Claes
AU - Mellström, Dan
AU - de Groot, Lisette C.P.G.M.
AU - Grant, Struan F.A.
AU - Kiel, Douglas P.
AU - Zillikens, M. Carola
AU - Rivadeneira, Fernando
AU - Sawcer, Stephen
AU - Timpson, Nicholas J.
AU - Richards, J. Brent
N1 - Publisher Copyright:
© 2017 American Society of Human Genetics
PY - 2017/8/3
Y1 - 2017/8/3
N2 - 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.
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.
KW - GWAS
KW - low-frequency genetic variants
KW - multiple sclerosis
KW - vitamin D
UR - http://www.scopus.com/inward/record.url?scp=85026218390&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2017.06.014
DO - 10.1016/j.ajhg.2017.06.014
M3 - Article
C2 - 28757204
AN - SCOPUS:85026218390
SN - 0002-9297
VL - 101
SP - 227
EP - 238
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -