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


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
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, JAJCauley@edc.pitt.eduJCAULEY
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: 30 Mar 2021 13:56
URI: http://d-scholarship.pitt.edu/id/eprint/24109

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