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

Thomas J Wang, 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, Thomas J Wang, 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

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).

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.

Copyright 2010 Elsevier Ltd. All rights reserved.

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.

Source: PubMed

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