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Low-frequency synonymous coding variation in CYP2R1 has large effects on Vitamin D levels and risk of multiple sclerosis
journal contributionposted on 2023-05-19, 09:58 authored by 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, DL, Nethander, M, Vandenput, L, Noordam, R, Forgetta, V, Greenwood, CMT, Biggs, ML, Psaty, BM, Rotter, JI, Zemel, BS, Mitchell, JA, Bruce TaylorBruce Taylor, Lorentzon, M, Karlsson, M, Jaddoe, VVW, Tiemeier, H, Campos-Obando, N, Franco, OH, Utterlinden, AG, Broer, L, van Schoor, NM, Ham, AC, Ikram, MA, Karasik, D, de Mutsert, R, Rosendaal, FR, den Heijer, M, Wang, TJ, Lind, L, Orwoll, ES, Mook-Kanamori, DO, Michaelsson, K, Kestenbaum, B, Ohlsson, C, Mellstrom, D, de Groot, LCPGM, Grant, SFA, Kiel, DP, Zillikens, MC, Rivadeneira, F, Sawcer, S, Timpson, NJ, Richards, JB
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.
Publication titleAmerican Journal of Human Genetics
Department/SchoolMenzies Institute for Medical Research
PublisherUniv Chicago Press
Place of publication1427 E 60Th St, Chicago, USA, Il, 60637-2954
Rights statement?Copyright 2017 American Society of Human Genetics.