04416nas a2200913 4500008004100000022001400041245012600055210006900181260001600250300001200266490000800278520169200286653003701978653002902015653001902044653003802063653001802101653003402119653001102153653002302164653003602187653001702223653001402240653002502254100002402279700001702303700001902320700001902339700001802358700002802376700002002404700002802424700001902452700003002471700002402501700002102525700002402546700002102570700002302591700002602614700001902640700002002659700002202679700002202701700002602723700001802749700002302767700002102790700002502811700002202836700002702858700002102885700002602906700001702932700002702949700002102976700002002997700001903017700002303036700002403059700002403083700002003107700001503127700002003142700002903162700002303191700002203214700001903236700002003255700003103275700002303306700002103329700002503350700002603375700002003401700002503421700002003446856003603466 2017 eng d a1537-660500aLow-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis.0 aLowFrequency Synonymous Coding Variation in CYP2R1 Has Large Eff c2017 Aug 03 a227-2380 v1013 a
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.
10aCholestanetriol 26-Monooxygenase10aCytochrome P450 Family 210aGene Frequency10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aHumans10aMultiple Sclerosis10aPolymorphism, Single Nucleotide10aRisk Factors10aVitamin D10aVitamin D Deficiency1 aManousaki, Despoina1 aDudding, Tom1 aHaworth, Simon1 aHsu, Yi-Hsiang1 aLiu, Ching-Ti1 aMedina-Gómez, Carolina1 aVoortman, Trudy1 avan der Velde, Nathalie1 aMelhus, Håkan1 aRobinson-Cohen, Cassianne1 aCousminer, Diana, L1 aNethander, Maria1 aVandenput, Liesbeth1 aNoordam, Raymond1 aForgetta, Vincenzo1 aGreenwood, Celia, M T1 aBiggs, Mary, L1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aZemel, Babette, S1 aMitchell, Jonathan, A1 aTaylor, Bruce1 aLorentzon, Mattias1 aKarlsson, Magnus1 aJaddoe, Vincent, V W1 aTiemeier, Henning1 aCampos-Obando, Natalia1 aFranco, Oscar, H1 aUtterlinden, Andre, G1 aBroer, Linda1 avan Schoor, Natasja, M1 aHam, Annelies, C1 aIkram, Arfan, M1 aKarasik, David1 ade Mutsert, Renée1 aRosendaal, Frits, R1 aHeijer, Martin, den1 aWang, Thomas, J1 aLind, Lars1 aOrwoll, Eric, S1 aMook-Kanamori, Dennis, O1 aMichaëlsson, Karl1 aKestenbaum, Bryan1 aOhlsson, Claes1 aMellström, Dan1 ade Groot, Lisette, C P G M1 aGrant, Struan, F A1 aKiel, Douglas, P1 aZillikens, Carola, M1 aRivadeneira, Fernando1 aSawcer, Stephen1 aTimpson, Nicholas, J1 aRichards, Brent uhttps://chs-nhlbi.org/node/7487