Genome-wide association study of circulating vitamin D levels

Jiyoung Ahn, 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 KraftDemetrius Albanes

Research output: Contribution to journalArticle

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 = 2.0 × 10-30), in linkage disequilibrium (LD) with rs7041, a non-synonymous SNP (D432E; P = 4.1 × 10-22) and rs1155563 (P = 3.8 × 10-25). 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 = 8.8 × 10-7], 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 = 3.3 × 10-7); 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 = 1.4 × 10-5). 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 = 1.8 × 10-49), NADSYN1/DHCR7 (P = 3.4 × 10-9) and CYP2R1 (P = 2.9 × 10-17), but not C10orf88 (P = 2.4 × 10-5). Published by Oxford University Press 2010.

Original languageEnglish (US)
Article numberddq155
Pages (from-to)2739-2745
Number of pages7
JournalHuman molecular genetics
Volume19
Issue number13
DOIs
StatePublished - Apr 23 2010

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Ahn, J., Yu, K., Stolzenberg-Solomon, R., Claire Simon, K., McCullough, M. L., Gallicchio, L., Jacobs, E. J., Ascherio, A., Helzlsouer, K., Jacobs, K. B., Li, Q., Weinstein, S. J., Purdue, M., Virtamo, J., Horst, R., Wheeler, W., Chanock, S., Hunter, D. J., Hayes, R. B., ... Albanes, D. (2010). Genome-wide association study of circulating vitamin D levels. Human molecular genetics, 19(13), 2739-2745. [ddq155]. https://doi.org/10.1093/hmg/ddq155