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Common genetic determinants of vitamin D insufficiency: a genome-wide association study.
Tuesday,2012-11-06 12:19 America/Los_Angeles — eenright
| Title | Common genetic determinants of vitamin D insufficiency: a genome-wide association study. |
| Publication Type | Journal Article |
| Year of Publication | 2010 |
| Authors | Wang, TJ, Zhang, F, J Richards, B, 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, C-L, 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, A-L, 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, J-O, Cauley, JA, Uitterlinden, AG, Gibson, Q, Jarvelin, M-R, Karasik, D, Siscovick, DS, Econs, MJ, Kritchevsky, SB, Florez, JC, Todd, JA, Dupuis, J, Hyppönen, E, Spector, TD |
| Journal | Lancet |
| Volume | 376 |
| Issue | 9736 |
| Pagination | 180-8 |
| Date Published | 2010 Jul 17 |
| ISSN | 1474-547X |
| Keywords | Canada, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 4, Cohort Studies, Dietary Supplements, Europe, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Heterozygote, Homozygote, Humans, Immunoassay, International Cooperation, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Seasons, United States, Vitamin D, Vitamin D Deficiency |
| Abstract | <p><b>BACKGROUND: </b>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.</p><p><b>METHODS: </b>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.</p><p><b>FINDINGS: </b>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.</p><p><b>INTERPRETATION: </b>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.</p><p><b>FUNDING: </b>Full funding sources listed at end of paper (see Acknowledgments).</p> |
| DOI | 10.1016/S0140-6736(10)60588-0 |
| Alternate Journal | Lancet |
| PubMed ID | 20541252 |
| PubMed Central ID | PMC3086761 |
| Grant List | N02-HL-6-4278 / HL / NHLBI NIH HHS / United States N01-HC-25195 / HC / NHLBI NIH HHS / United States N01 HC085086 / HC / NHLBI NIH HHS / United States P01 AG-18397 / AG / NIA NIH HHS / United States RL1 MH083268-01 / MH / NIMH NIH HHS / United States M01 RR000069-39 / RR / NCRR NIH HHS / United States R01 AR046838 / AR / NIAMS NIH HHS / United States N01-AG-6-2101 / AG / NIA NIH HHS / United States R01 AG027002-04 / AG / NIA NIH HHS / United States MC_UP_A100_1003 / / Medical Research Council / United Kingdom N01 HC085081 / HC / NHLBI NIH HHS / United States U01 HL080295-04 / HL / NHLBI NIH HHS / United States R01 HL087652-03 / HL / NHLBI NIH HHS / United States N01 AG062101 / AG / NIA NIH HHS / United States G0801462 / / Medical Research Council / United Kingdom R01 AG032098-03 / AG / NIA NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States R01 HL087679 / HL / NHLBI NIH HHS / United States R01-AG032098 / AG / NIA NIH HHS / United States G20234 / / Biotechnology and Biological Sciences Research Council / United Kingdom GR069224 / / Wellcome Trust / United Kingdom N01 HC075150 / HC / NHLBI NIH HHS / United States N01-HC-85081 / HC / NHLBI NIH HHS / United States N01-AG-6-2103 / AG / NIA NIH HHS / United States N01 HC015103 / HC / NHLBI NIH HHS / United States M01 RR000069 / RR / NCRR NIH HHS / United States 079895 / / Wellcome Trust / United Kingdom N01 HC085083 / HC / NHLBI NIH HHS / United States P30 DK063491-06 / DK / NIDDK NIH HHS / United States R01 AR046838-05 / AR / NIAMS NIH HHS / United States R01 HL087679-02 / HL / NHLBI NIH HHS / United States N01 HC025195 / HC / NHLBI NIH HHS / United States G0601653 / / Medical Research Council / United Kingdom P01 AG018397-05 / AG / NIA NIH HHS / United States M01 RR000750-33 / RR / NCRR NIH HHS / United States N02 HL64278 / HL / NHLBI NIH HHS / United States N01 HC085085 / HC / NHLBI NIH HHS / United States R01 AG029364 / AG / NIA NIH HHS / United States / / Department of Health / United Kingdom M01 RR-00750 / RR / NCRR NIH HHS / United States 1RL1MH083268-01 / MH / NIMH NIH HHS / United States R01 HL087652 / HL / NHLBI NIH HHS / United States R01 AR/AG 41398 / AG / NIA NIH HHS / United States N01 AG062106 / AG / NIA NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States N01-HC-85086 / HC / NHLBI NIH HHS / United States R01 AR041398 / AR / NIAMS NIH HHS / United States R01 AG041517 / AG / NIA NIH HHS / United States R01 AG029364-03S1 / AG / NIA NIH HHS / United States G0500539 / / Medical Research Council / United Kingdom N01HC85086 / HL / NHLBI NIH HHS / United States 076113 / / Wellcome Trust / United Kingdom P01 AG018397 / AG / NIA NIH HHS / United States M01 RR000750 / RR / NCRR NIH HHS / United States MC_UP_A620_1014 / / Medical Research Council / United Kingdom R01 AR46838 / AR / NIAMS NIH HHS / United States R01 AG032098 / AG / NIA NIH HHS / United States R01 DK033651 / DK / NIDDK NIH HHS / United States MC_U106179471 / / Medical Research Council / United Kingdom N01 HC085082 / HC / NHLBI NIH HHS / United States N01-HC-85082 / HC / NHLBI NIH HHS / United States U01 DK062418 / DK / NIDDK NIH HHS / United States AG14759 / AG / NIA NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States N01 HC085080 / HC / NHLBI NIH HHS / United States HHSN268200782096C / HG / NHGRI NIH HHS / United States / / Intramural NIH HHS / United States / / Canadian Institutes of Health Research / Canada P30 DK072488 / DK / NIDDK NIH HHS / United States PHCS/C4/4/016 / / Department of Health / United Kingdom N01 HC055222 / HC / NHLBI NIH HHS / United States N01 AG062103 / AG / NIA NIH HHS / United States G0701863 / / Medical Research Council / United Kingdom N01-HC-55222 / HC / NHLBI NIH HHS / United States M01RR00069 / RR / NCRR NIH HHS / United States N01-HC-85083 / HC / NHLBI NIH HHS / United States N01-HC-75150 / HC / NHLBI NIH HHS / United States N01-HC-85080 / HC / NHLBI NIH HHS / United States R01 HL084443 / HL / NHLBI NIH HHS / United States N01-AG-6-2106 / AG / NIA NIH HHS / United States R01 AG027002 / AG / NIA NIH HHS / United States U01 DK062418-06 / DK / NIDDK NIH HHS / United States / / Arthritis Research UK / United Kingdom N01 HC085084 / HC / NHLBI NIH HHS / United States R01-AG029364 / AG / NIA NIH HHS / United States N01HC75150 / HL / NHLBI NIH HHS / United States R01 AG014759 / AG / NIA NIH HHS / United States N01HC25195 / HL / NHLBI NIH HHS / United States DK063491 / DK / NIDDK NIH HHS / United States N01-HC-85079 / HC / NHLBI NIH HHS / United States 068545/Z/02 / / Wellcome Trust / United Kingdom HHSN268200782096C / / PHS HHS / United States 5R01HL087679-02 / HL / NHLBI NIH HHS / United States RL1 MH083268 / MH / NIMH NIH HHS / United States R01 HL084443-03 / HL / NHLBI NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States N01 HC085079 / HC / NHLBI NIH HHS / United States 061858 / / Wellcome Trust / United Kingdom MC_U106188470 / / Medical Research Council / United Kingdom R01 AG014759-03 / AG / NIA NIH HHS / United States N01 HC045133 / HC / NHLBI NIH HHS / United States G0000934 / / Medical Research Council / United Kingdom N01 HC035129 / HC / NHLBI NIH HHS / United States R01 AG032098-02 / AG / NIA NIH HHS / United States R01 AR041398-16A1 / AR / NIAMS NIH HHS / United States G0600705 / / Medical Research Council / United Kingdom |