학술논문
Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis
Document Type
Author
Manousaki, D.; Dudding, T.; Haworth, S.; Hsu, Y. H.; Liu, C. T.; Medina-Gomez, C.; Voortman, T.; van der Velde, N.; Melhus, H.; Robinson-Cohen, C.; Cousminer, D. L.; Nethander, Maria, 1980; Vandenput, Liesbeth, 1974; Noordam, R.; Forgetta, V.; Greenwood, C. M. T.; Biggs, M. L.; Psaty, B. M.; Rotter, J. I.; Zemel, B. S.; Taylor, B.; Lorentzon, Mattias, 1970; Karlsson, M.; Jaddoe, V. V. W.; Tiemeier, H.; Campos-Obando, N.; Franco, O. H.; Utterlinden, A. G.; Broer, L.; van Schoor, N. M.; Ham, A. C.; Ikram, M. A.; Karasik, D.; de Mutsert, R.; Rosendaal, F. R.; den Heijer, M.; Wang, T. J.; Lind, L.; Orwoll, E. S.; Mook-Kanamori, D. O.; Michaelsson, K.; Kestenbaum, B.; Ohlsson, Claes, 1965; Mellström, Dan, 1945; de Groot, Lcpgm; Grant, S. F. A.; Kiel, D. P.; Zillikens, M. C.; Rivadeneira, F.; Sawcer, S.; Timpson, N. J.; Richards, J. B.; Sella Sj, Journal Of Pediatrics V. P.
Source
American Journal of Human Genetics. 101(2):227-238
Subject
Language
English
ISSN
0002-9297
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 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.