Genome-wide association study of circulating vitamin D levels

Hum Mol Genet. 2010 Jul 1;19(13):2739-45. doi: 10.1093/hmg/ddq155. Epub 2010 Apr 23.

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)).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acyl-CoA Dehydrogenase / genetics*
  • Amide Synthases / genetics*
  • Cholestanetriol 26-Monooxygenase / genetics*
  • Cytochrome P450 Family 2
  • European Continental Ancestry Group / genetics
  • Genome-Wide Association Study
  • Humans
  • Linkage Disequilibrium
  • Oxidoreductases Acting on CH-CH Group Donors / genetics*
  • Polymorphism, Single Nucleotide
  • Vitamin D / analogs & derivatives*
  • Vitamin D / blood
  • Vitamin D / genetics
  • Vitamin D-Binding Protein / genetics*

Substances

  • Vitamin D-Binding Protein
  • Vitamin D
  • 25-hydroxyvitamin D
  • Cytochrome P450 Family 2
  • CYP2R1 protein, human
  • Cholestanetriol 26-Monooxygenase
  • Oxidoreductases Acting on CH-CH Group Donors
  • 7-dehydrocholesterol reductase
  • Acyl-CoA Dehydrogenase
  • Amide Synthases
  • NAD+ synthase