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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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 | | | |
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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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