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Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis.
Wednesday,2017-10-25 14:15 America/Los_Angeles — ecterry
| Title | Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis. |
| Publication Type | Journal Article |
| Year of Publication | 2017 |
| Authors | Manousaki, D, Dudding, T, Haworth, S, Hsu, Y-H, Liu, C-T, Medina-Gómez, 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, Taylor, B, Lorentzon, M, Karlsson, M, Jaddoe, VVW, Tiemeier, H, Campos-Obando, N, Franco, OH, Utterlinden, AG, Broer, L, van Schoor, NM, Ham, AC, Ikram, AM, Karasik, D, de Mutsert, R, Rosendaal, FR, Heijer, Mden, Wang, TJ, Lind, L, Orwoll, ES, Mook-Kanamori, DO, Michaëlsson, K, Kestenbaum, B, Ohlsson, C, Mellström, D, de Groot, LCPGM, Grant, SFA, Kiel, DP, Zillikens, CM, Rivadeneira, F, Sawcer, S, Timpson, NJ, J Richards, B |
| Journal | Am J Hum Genet |
| Volume | 101 |
| Issue | 2 |
| Pagination | 227-238 |
| Date Published | 2017 Aug 03 |
| ISSN | 1537-6605 |
| Keywords | Cholestanetriol 26-Monooxygenase, Cytochrome P450 Family 2, Gene Frequency, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Multiple Sclerosis, Polymorphism, Single Nucleotide, Risk Factors, Vitamin D, Vitamin D Deficiency |
| Abstract | <p>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.</p> |
| DOI | 10.1016/j.ajhg.2017.06.014 |
| Alternate Journal | Am. J. Hum. Genet. |
| PubMed ID | 28757204 |
| PubMed Central ID | PMC5544392 |
| Grant List | R01 HL105756 / HL / NHLBI NIH HHS / United States U01 HL130114 / HL / NHLBI NIH HHS / United States |
ePub date:
17/08