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Low-frequency synonymous coding variation in CYP2R1 has large effects on Vitamin D levels and risk of multiple sclerosis


Manousaki, D and Dudding, T and Haworth, S and Hsu, Y-H and Liu, C-T and Medina-Gomez, C and Voortman, T and van der Velde, N and Melhus, H and Robinson-Cohen, C and Cousminer, DL and Nethander, M and Vandenput, L and Noordam, R and Forgetta, V and Greenwood, CMT and Biggs, ML and Psaty, BM and Rotter, JI and Zemel, BS and Mitchell, JA and Taylor, B and Lorentzon, M and Karlsson, M and Jaddoe, VVW and Tiemeier, H and Campos-Obando, N and Franco, OH and Utterlinden, AG and Broer, L and van Schoor, NM and Ham, AC and Ikram, MA and Karasik, D and de Mutsert, R and Rosendaal, FR and den Heijer, M and Wang, TJ and Lind, L and Orwoll, ES and Mook-Kanamori, DO and Michaelsson, K and Kestenbaum, B and Ohlsson, C and Mellstrom, D and de Groot, LCPGM and Grant, SFA and Kiel, DP and Zillikens, MC and Rivadeneira, F and Sawcer, S and Timpson, NJ and Richards, JB, Low-frequency synonymous coding variation in CYP2R1 has large effects on Vitamin D levels and risk of multiple sclerosis, American Journal of Human Genetics, 101, (2) pp. 227-238. ISSN 0002-9297 (2017) [Refereed Article]

Copyright Statement

Copyright 2017 American Society of Human Genetics.

DOI: doi:10.1016/j.ajhg.2017.06.014


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] = 1.7-2.78, p = 1.26 x10 -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 x 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.

Item Details

Item Type:Refereed Article
Keywords:GWAS, low-frequency genetic variants, multiple sclerosis, vitamin D
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Central nervous system
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Taylor, B (Professor Bruce Taylor)
ID Code:120264
Year Published:2017
Web of Science® Times Cited:72
Deposited By:Menzies Institute for Medical Research
Deposited On:2017-08-17
Last Modified:2022-08-23

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