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Meta-Analysis
. 2010 Jul 17;376(9736):180-8.
doi: 10.1016/S0140-6736(10)60588-0. Epub 2010 Jun 10.

Common genetic determinants of vitamin D insufficiency: a genome-wide association study

Thomas J Wang  1 , Feng Zhang, J Brent Richards, Bryan Kestenbaum, Joyce B van Meurs, Diane Berry, Douglas P Kiel, Elizabeth A Streeten, Claes Ohlsson, Daniel L Koller, Leena Peltonen, Jason D Cooper, Paul F O'Reilly, Denise K Houston, Nicole L Glazer, Liesbeth Vandenput, Munro Peacock, Julia Shi, Fernando Rivadeneira, Mark I McCarthy, Pouta Anneli, Ian H de Boer, Massimo Mangino, Bernet Kato, Deborah J Smyth, Sarah L Booth, Paul F Jacques, Greg L Burke, Mark Goodarzi, Ching-Lung Cheung, Myles Wolf, Kenneth Rice, David Goltzman, Nick Hidiroglou, Martin Ladouceur, Nicholas J Wareham, Lynne J Hocking, Deborah Hart, Nigel K Arden, Cyrus Cooper, Suneil Malik, William D Fraser, Anna-Liisa Hartikainen, Guangju Zhai, Helen M Macdonald, Nita G Forouhi, Ruth J F Loos, David M Reid, Alan Hakim, Elaine Dennison, Yongmei Liu, Chris Power, Helen E Stevens, Laitinen Jaana, Ramachandran S Vasan, Nicole Soranzo, Jörg Bojunga, Bruce M Psaty, Mattias Lorentzon, Tatiana Foroud, Tamara B Harris, Albert Hofman, John-Olov Jansson, Jane A Cauley, Andre G Uitterlinden, Quince Gibson, Marjo-Riitta Järvelin, David Karasik, David S Siscovick, Michael J Econs, Stephen B Kritchevsky, Jose C Florez, John A Todd, Josee Dupuis, Elina Hyppönen, Timothy D Spector
Affiliations
Meta-Analysis

Common genetic determinants of vitamin D insufficiency: a genome-wide association study

Thomas J Wang et al. Lancet. .

Abstract

Background: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency.

Methods: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants.

Findings: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile.

Interpretation: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency.

Funding: Full funding sources listed at end of paper (see Acknowledgments).

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Conflict of interest statement

Author Disclosures: TJW has served on the scientific advisory board of Diasorin. None of the other authors report conflicts of interest relevant to this manuscript.

Figures

Figure 1
Figure 1
Regional linkage disequilibrium plots for SNPs at GC (panel 1A), DHCR7/NADSYN1 (panel 1B), CYP2R1 (panel 1C), and CYP24A1 (panel 1D).
Figure 1
Figure 1
Regional linkage disequilibrium plots for SNPs at GC (panel 1A), DHCR7/NADSYN1 (panel 1B), CYP2R1 (panel 1C), and CYP24A1 (panel 1D).
Figure 1
Figure 1
Regional linkage disequilibrium plots for SNPs at GC (panel 1A), DHCR7/NADSYN1 (panel 1B), CYP2R1 (panel 1C), and CYP24A1 (panel 1D).
Figure 1
Figure 1
Regional linkage disequilibrium plots for SNPs at GC (panel 1A), DHCR7/NADSYN1 (panel 1B), CYP2R1 (panel 1C), and CYP24A1 (panel 1D).
Figure 2
Figure 2
Risk of vitamin D insufficiency (using threshold of 75 nmol/L), according to quartile of genotype score. Bars indicate 95% confidence intervals.
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