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Genome-wide association study of circulating vitamin D levels -May 2010

Jiyoung Ahn1,13, Kai Yu2,13, Rachael Stolzenberg-Solomon2, K. Claire Simon3, Marjorie L. McCullough4, Lisa Gallicchio5, Eric J. Jacobs4, Alberto Ascherio3,6,7, Kathy Helzlsouer5, Kevin B. Jacobs2, Qizhai Li8, Stephanie J. Weinstein2, Mark Purdue2, Jarmo Virtamo9, Ronald Horst10, William Wheeler11, Stephen Chanock2, David J. Hunter3,6,12, Richard B. Hayes1, Peter Kraft6,12 and Demetrius Albanes2,*

1 Division of Epidemiology, Department of Environmental Medicine, New York University School of Medicine, New York, NY, 10016, USA 2 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA 3 Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, 02115, USA 4 Department of Epidemiology, American Cancer Society, 250 Williams Street, NW, Atlanta, Georgia 30303-1002, USA 5 Prevention and Research Center, The Weinberg Center for Women's Health and Medicine, Mercy Medical Center, Baltimore, Maryland, 21202 USA 6 Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, 02115, USA 7 Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA 8 Key Laboratory of Systems and Control, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, People's Republic of China 9 Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, FIN-00300 Finland 10 Heartland Assays, Inc., Ames, Iowa, USA 11 Information Management Services, Rockville, MD, USA 12 Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, 02115, USA
To whom correspondence should be addressed: Demetrius Albanes, Division of Cancer Epidemiology and Genetics, EPS-320, National Cancer Institute, NIH, Bethesda, Maryland, 20892, USA, Phone: 01 3015942869 Fax: 01 3014966829, Email: daa at nih.gov
Received December 23, 2009; Revised April 14, 2010; Accepted April 16, 2010

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 4,501 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 x 10–30), in LD with rs7041, a nonsynonymous SNP (D432E; P=4.1 x 10-22), and rs1155563 (P = 3.8 x 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 x 10-7), which was in high LD with rs1790349, located in DHCR7, the gene encoding 7-dehydrocholesterol reductase which 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 x 10-7); and, rs2060793 on chromosome 11p15.2 in CYP2R1 (encoding a key C-25-hydroxylase that converts vitamin D3 to an active vitamin D receptor ligand; P=1.4 x 10–5). We genotyped SNPs in these four regions in 2,221 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 x 10-49), NADSYN1/DHCR7 (P=3.4 x 10-9), and CYP2R1 (P=2.9 x 10-17), but not C10orf88 (P=2.4 x 10-5).

13 These authors contributed equally to this work.

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