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Meta-Analysis
. 2017 Aug 3;101(2):227-238.
doi: 10.1016/j.ajhg.2017.06.014. Epub 2017 Jul 27.

Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis

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Free PMC article
Meta-Analysis

Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis

Despoina Manousaki et al. Am J Hum Genet. .
Free PMC article

Erratum in

  • Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis.
    Manousaki D, Dudding T, Haworth S, Hsu YH, Liu CT, 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 MA, Karasik D, de Mutsert R, Rosendaal FR, den Heijer M, 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 MC, Rivadeneira F, Sawcer S, Timpson NJ, Richards JB. Manousaki D, et al. Am J Hum Genet. 2018 Dec 6;103(6):1053. doi: 10.1016/j.ajhg.2018.11.010. Am J Hum Genet. 2018. PMID: 30526863 Free PMC article. No abstract available.

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 × 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.

Keywords: GWAS; low-frequency genetic variants; multiple sclerosis; vitamin D.

Figures

Figure 1
Figure 1
Schematic of the Discovery Single-Variant Meta-analysis
Figure 2
Figure 2
Discovery Single-Variant Meta-analysis (A) Quantile-quantile plot for the single SNV meta-analysis. (B) Manhattan plot of the meta-analysis depicts variants with MAF > 0.5% across the 22 autosomes against the −log10 p value from the meta-analysis of 19 cohorts, which included 42,274 individuals.
Figure 3
Figure 3
Forest Plot by Cohort for rs117913124 and Forest Plot for rs117913124 and the Previously Described Common 25OHD-Related Variants from Discovery Meta-analysis (A) Forest plot of estimates from all 19 studies for the low-frequency CYP2R1 variant rs117913124. (B) Forest plot of the effect of the four common SUNLIGHT variants and the CYP2R1 low-frequency variant rs117913124 on log-transformed 25OHD levels. Squares represent beta values in the 19 studies, and bars around the squares represent 95% confidence intervals (CIs).
Figure 4
Figure 4
Association Signals from 11p.15.2 (A) UCSC Genome Browser snapshot including the top low-frequency SNVs (see Table 2) and the lead common variant rs10741657 in CYP2R1. The position of rs117913124 is highlighted in light blue. (B) Regional disequilibrium plot showing rs117913124 (purple dot), its perfect proxy rs11670203 (red dot), and the other genome-wide-significant SNVs in the same locus (blue and green dots). The plot depicts SNVs within 1 Mb of a locus’s lead SNV (x axis) and their associated meta-analysis p value (−log10) (see Table S10 for more details). SNVs are color coded according to r2 with the lead SNV (labeled; r2 was calculated from the UK10K WGS dataset). The recombination rate (blue line), position of genes and their exons, and direction of transcription are also displayed (below plot). (C) Linkage-disequilibrium plot indicating the r2 values between the SNVs of Table 2 (top low-frequency variants) and between these low-frequency SNVs and the lead common variant (rs107416570) at the same CYP2R1 locus (r2 calculated from the 1000 Genomes dataset).
Figure 5
Figure 5
Effect of rs117913124 on Vitamin D Insufficiency Forest plot of the effect of the low-frequency CYP2R1 variant rs117913124 on vitamin D insufficiency in four studies. Squares represent odds ratios for vitamin D insufficiency in the four studies, and bars represent 95% CIs.
Figure 6
Figure 6
Association Signals from Chromosomes 12 and 14 Forest plots with (A) estimates for the chromosome 12 common variant rs3819817 and (B) estimates for the chromosome 14 common variant rs2277458 from all 19 studies of the meta-analysis where both variants were present. Squares represent beta values in the 19 studies, and bars around the squares represent 95% CIs.
Figure 7
Figure 7
Schematic of the Vitamin D Metabolic Pathway UVB, ultraviolet B rays.

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