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

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dc.contributor.authorWang, T.
dc.contributor.authorZhang, F.
dc.contributor.authorRichards, J.B.
dc.contributor.authorKestenbaum, B.
dc.contributor.authorHypponen, E.
dc.contributor.authorSpector, T.D.
dc.date.issued2010
dc.descriptionLink to a related website: http://europepmc.org/articles/pmc3086761?pdf=render, Open Access via Unpaywall
dc.description.abstractBackground: 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.
dc.identifier.citationThe Lancet, 2010; 376(9736):180-188
dc.identifier.doi10.1016/S0140-6736(10)60588-0
dc.identifier.issn0140-6736
dc.identifier.issn1474-547X
dc.identifier.urihttps://hdl.handle.net/1959.8/154382
dc.language.isoen
dc.publisherThe Lancet Publishing Group
dc.relation.fundingNIH/NHLBI N01-HC-25195
dc.relation.fundingUK Medical Research Council , Project: G0601653
dc.relation.fundingUS Department of Agriculture, Agricultural Research Service 58-1950-7-707)
dc.relation.fundingNational Institute of Aging AG14759
dc.relation.fundingNational Institute on Aging R01 AR/AG 41398
dc.relation.fundingNational Center for Research Resources M01RR00069
dc.rightsCopyright 2010 Elsevier
dc.source.urihttps://doi.org/10.1016/S0140-6736(10)60588-0
dc.subjectChromosomes, Human, Pair 4
dc.subjectChromosomes, Human, Pair 11
dc.subjectHumans
dc.subjectVitamin D Deficiency
dc.subjectGenetic Predisposition to Disease
dc.subjectVitamin D
dc.subjectImmunoassay
dc.subjectCohort Studies
dc.subjectSeasons
dc.subjectHeterozygote
dc.subjectHomozygote
dc.subjectLinkage Disequilibrium
dc.subjectPolymorphism, Single Nucleotide
dc.subjectInternational Cooperation
dc.subjectDietary Supplements
dc.subjectCanada
dc.subjectUnited States
dc.subjectEurope
dc.subjectGenome-Wide Association Study
dc.subjectWhite People
dc.titleCommon genetic determinants of vitamin D insufficiency : a genome-wide association study
dc.typeJournal article
pubs.publication-statusPublished
ror.mmsid9915910389501831

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