Genome-wide association study of circulating vitamin D levels.
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)).
Ahn
Jiyoung
J
Department of Environmental Medicine, New York University School of Medicine, New York, NY 10016, USA.
Yu
Kai
K
Stolzenberg-Solomon
Rachael
R
Simon
K Claire
KC
McCullough
Marjorie L
ML
Gallicchio
Lisa
L
Jacobs
Eric J
EJ
Ascherio
Alberto
A
Helzlsouer
Kathy
K
Jacobs
Kevin B
KB
Li
Qizhai
Q
Weinstein
Stephanie J
SJ
Purdue
Mark
M
Virtamo
Jarmo
J
Horst
Ronald
R
Wheeler
William
W
Chanock
Stephen
S
Hunter
David J
DJ
Hayes
Richard B
RB
Kraft
Peter
P
Albanes
Demetrius
D
D042964:Acyl-CoA Dehydrogenase / Q000235:genetics*; D019732:Amide Synthases / Q000235:genetics*; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics*; D000072467:Cytochrome P450 Family 2; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood / Q000235:genetics; D014809:Vitamin D-Binding Protein / Q000235:genetics*; D044465:White People / Q000235:genetics
D014809:Vitamin D-Binding Protein; D014807:Vitamin D; C104450:25-hydroxyvitamin D; D000072467:Cytochrome P450 Family 2; C506833:CYP2R1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase; D042964:Acyl-CoA Dehydrogenase; D019732:Amide Synthases; C038479:NAD+ synthase