Genome-wide association study of circulating vitamin D levels - PubMed (original) (raw)
. 2010 Jul 1;19(13):2739-45.
doi: 10.1093/hmg/ddq155. Epub 2010 Apr 23.
Kai Yu, Rachael Stolzenberg-Solomon, K Claire Simon, Marjorie L McCullough, Lisa Gallicchio, Eric J Jacobs, Alberto Ascherio, Kathy Helzlsouer, Kevin B Jacobs, Qizhai Li, Stephanie J Weinstein, Mark Purdue, Jarmo Virtamo, Ronald Horst, William Wheeler, Stephen Chanock, David J Hunter, Richard B Hayes, Peter Kraft, Demetrius Albanes
Affiliations
- PMID: 20418485
- PMCID: PMC2883344
- DOI: 10.1093/hmg/ddq155
Genome-wide association study of circulating vitamin D levels
Jiyoung Ahn et al. Hum Mol Genet. 2010.
Abstract
The primary circulating form of vitamin D, 25-hydroxy-vitamin D [25(OH)D], is associated with multiple medical outcomes, including rickets, osteoporosis, multiple sclerosis and cancer. In a genome-wide association study (GWAS) of 4501 persons of European ancestry drawn from five cohorts, we identified single-nucleotide polymorphisms (SNPs) in the gene encoding group-specific component (vitamin D binding) protein, GC, on chromosome 4q12-13 that were associated with 25(OH)D concentrations: rs2282679 (P=2.0x10(-30)), in linkage disequilibrium (LD) with rs7041, a non-synonymous SNP (D432E; P=4.1x10(-22)) and rs1155563 (P=3.8x10(-25)). Suggestive signals for association with 25(OH)D were also observed for SNPs in or near three other genes involved in vitamin D synthesis or activation: rs3829251 on chromosome 11q13.4 in NADSYN1 [encoding nicotinamide adenine dinucleotide (NAD) synthetase; P=8.8x10(-7)], which was in high LD with rs1790349, located in DHCR7, the gene encoding 7-dehydrocholesterol reductase that synthesizes cholesterol from 7-dehydrocholesterol; rs6599638 in the region harboring the open-reading frame 88 (C10orf88) on chromosome 10q26.13 in the vicinity of ACADSB (acyl-Coenzyme A dehydrogenase), involved in cholesterol and vitamin D synthesis (P=3.3x10(-7)); and rs2060793 on chromosome 11p15.2 in CYP2R1 (cytochrome P450, family 2, subfamily R, polypeptide 1, encoding a key C-25 hydroxylase that converts vitamin D3 to an active vitamin D receptor ligand; P=1.4x10(-5)). We genotyped SNPs in these four regions in 2221 additional samples and confirmed strong genome-wide significant associations with 25(OH)D through meta-analysis with the GWAS data for GC (P=1.8x10(-49)), NADSYN1/DHCR7 (P=3.4x10(-9)) and CYP2R1 (P=2.9x10(-17)), but not C10orf88 (P=2.4x10(-5)).
Figures
Figure 1.
Genome-wide associations of circulating 25-hydroxy vitamin D graphed by chromosome position and −log10 _P_-value based on the five GWAS cohorts (n = 4501). Only P values of >10−16 are plotted, with the most significant variants in the GC gene on chromosome 4 not being shown (rs2282679, rs1155563 and rs7041; _P_-values of 1.96 × 10−30, 3.56 × 10−25 and 4.07 × 10−22, respectively).
Figure 2.
Quantile–quantile plot of 593 253 SNPs from the meta-analysis of the five GWAS scans (n = 4501). Each blue dot represents an observed statistic [defined as the −log10(P)] versus the corresponding expected statistic. The blue dots correspond to the distribution of test statistics. The black line corresponds to the null distribution. Observed _P_-values <10−16 are plotted at the 10−16 significance level.
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References
- Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academies Press; 1999. - PubMed
- DeLuca H.F., Zierold C. Mechanisms and functions of vitamin D. Nutr. Rev. 1998;56:S4–S10. - PubMed
- Lin R., White J.H. The pleiotropic actions of vitamin D. Bioessays. 2004;26:21–28. doi:10.1002/bies.10368. - DOI - PubMed
- Hunter D., De Lange M., Snieder H., MacGregor A.J., Swaminathan R., Thakker R.V., Spector T.D. Genetic contribution to bone metabolism, calcium excretion, and vitamin D and parathyroid hormone regulation. J. Bone Miner. Res. 2001;16:371–378. doi:10.1359/jbmr.2001.16.2.371. - DOI - PubMed
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