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

Wang, TJ and Zhang, F and Richards, JB and Kestenbaum, B and Van Meurs, JB and Berry, D and Kiel, DP and Streeten, EA and Ohlsson, C and Koller, DL and Peltonen, L and Cooper, JD and O'Reilly, PF and Houston, DK and Glazer, NL and Vandenput, L and Peacock, M and Shi, J and Rivadeneira, F and McCarthy, MI and Anneli, P and De Boer, IH and Mangino, M and Kato, B and Smyth, DJ and Booth, SL and Jacques, PF and Burke, GL and Goodarzi, M and Cheung, CL and Wolf, M and Rice, K and Goltzman, D and Hidiroglou, N and Ladouceur, M and Wareham, NJ and Hocking, LJ and Hart, D and Arden, NK and Cooper, C and Malik, S and Fraser, WD and Hartikainen, AL and Zhai, G and Macdonald, HM and Forouhi, NG and Loos, RJF and Reid, DM and Hakim, A and Dennison, E and Liu, Y and Power, C and Stevens, HE and Jaana, L and Vasan, RS and Soranzo, N and Bojunga, J and Psaty, BM and Lorentzon, M and Foroud, T and Harris, TB and Hofman, A and Jansson, JO and Cauley, JA and Uitterlinden, AG and Gibson, Q and Järvelin, MR and Karasik, D and Siscovick, DS and Econs, MJ and Kritchevsky, SB and Florez, JC and Todd, JA and Dupuis, J and Hyppönen, E and Spector, TD (2010) Common genetic determinants of vitamin D insufficiency: A genome-wide association study. The Lancet, 376 (9736). 180 - 188. ISSN 0140-6736

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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=1·9×10-109 for rs2282679, in GC); 11q12 (p=2·1×10-27 for rs12785878, near DHCR7); and 11p15 (p=3·3×10-20 for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6·0×10-10 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= 2·3×10-48) or lower than 50 nmol/L (1·92, 1·70-2·16, p=1·0×10-26) 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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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Wang, TJ Zhang, F Richards, JB Kestenbaum, B Van Meurs, JB Berry, D Kiel, DP Streeten, EA Ohlsson, C Koller, DL Peltonen, L Cooper, JD O'Reilly, PF Houston, DK Glazer, NL Vandenput, L Peacock, M Shi, J Rivadeneira, F McCarthy, MI Anneli, P De Boer, IH Mangino, M Kato, B Smyth, DJ Booth, SL Jacques, PF Burke, GL Goodarzi, M Cheung, CL Wolf, M Rice, K Goltzman, D Hidiroglou, N Ladouceur, M Wareham, NJ Hocking, LJ Hart, D Arden, NK Cooper, C Malik, S Fraser, WD Hartikainen, AL Zhai, G Macdonald, HM Forouhi, NG Loos, RJF Reid, DM Hakim, A Dennison, E Liu, Y Power, C Stevens, HE Jaana, L Vasan, RS Soranzo, N Bojunga, J Psaty, BM Lorentzon, M Foroud, T Harris, TB Hofman, A Jansson, JO Cauley, JA JCauley@edc.pitt.edu JCAULEY Uitterlinden, AG Gibson, Q Järvelin, MR Karasik, D Siscovick, DS Econs, MJ Kritchevsky, SB Florez, JC Todd, JA Dupuis, J Hyppönen, E Spector, TD
Date:	1 January 2010
Date Type:	Publication
Journal or Publication Title:	The Lancet
Volume:	376
Number:	9736
Page Range:	180 - 188
DOI or Unique Handle:	10.1016/s0140-6736(10)60588-0
Schools and Programs:	Graduate School of Public Health > Epidemiology
Refereed:	Yes
ISSN:	0140-6736
Date Deposited:	07 May 2015 20:38
Last Modified:	22 Jun 2021 13:56
URI:	http://d-scholarship.pitt.edu/id/eprint/24109

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