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

TitleCommon genetic determinants of vitamin D insufficiency: A genome-wide association study
Authors
Issue Date2010
PublisherThe Lancet Publishing Group. The Journal's web site is located at http://www.elsevier.com/locate/lancet
Citation
The Lancet, 2010, v. 376 n. 9736, p. 180-188 How to Cite?
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. Funding Full funding sources listed at end of paper (see Acknowledgments). ].
Persistent Identifierhttp://hdl.handle.net/10722/183386
ISSN
2015 Impact Factor: 44.002
2015 SCImago Journal Rankings: 14.638
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorWang, TJen_US
dc.contributor.authorZhang, Fen_US
dc.contributor.authorRichards, JBen_US
dc.contributor.authorKestenbaum, Ben_US
dc.contributor.authorVan Meurs, JBen_US
dc.contributor.authorBerry, Den_US
dc.contributor.authorKiel, DPen_US
dc.contributor.authorStreeten, EAen_US
dc.contributor.authorOhlsson, Cen_US
dc.contributor.authorKoller, DLen_US
dc.contributor.authorPeltonen, Len_US
dc.contributor.authorCooper, JDen_US
dc.contributor.authorO'reilly, PFen_US
dc.contributor.authorHouston, DKen_US
dc.contributor.authorGlazer, NLen_US
dc.contributor.authorVandenput, Len_US
dc.contributor.authorPeacock, Men_US
dc.contributor.authorShi, Jen_US
dc.contributor.authorRivadeneira, Fen_US
dc.contributor.authorMccarthy, MIen_US
dc.contributor.authorAnneli, Pen_US
dc.contributor.authorDe Boer, IHen_US
dc.contributor.authorMangino, Men_US
dc.contributor.authorKato, Ben_US
dc.contributor.authorSmyth, DJen_US
dc.contributor.authorBooth, SLen_US
dc.contributor.authorJacques, PFen_US
dc.contributor.authorBurke, GLen_US
dc.contributor.authorGoodarzi, Men_US
dc.contributor.authorCheung, CLen_US
dc.contributor.authorWolf, Men_US
dc.contributor.authorRice, Ken_US
dc.contributor.authorGoltzman, Den_US
dc.contributor.authorHidiroglou, Nen_US
dc.contributor.authorLadouceur, Men_US
dc.contributor.authorWareham, NJen_US
dc.contributor.authorHocking, LJen_US
dc.contributor.authorHart, Den_US
dc.contributor.authorArden, NKen_US
dc.contributor.authorCooper, Cen_US
dc.contributor.authorMalik, Sen_US
dc.contributor.authorFraser, WDen_US
dc.contributor.authorHartikainen, ALen_US
dc.contributor.authorZhai, Gen_US
dc.contributor.authorMacdonald, HMen_US
dc.contributor.authorForouhi, NGen_US
dc.contributor.authorLoos, RJFen_US
dc.contributor.authorReid, DMen_US
dc.contributor.authorHakim, Aen_US
dc.contributor.authorDennison, Een_US
dc.contributor.authorLiu, Yen_US
dc.contributor.authorPower, Cen_US
dc.contributor.authorStevens, HEen_US
dc.contributor.authorJaana, Len_US
dc.contributor.authorVasan, RSen_US
dc.contributor.authorSoranzo, Nen_US
dc.contributor.authorBojunga, Jen_US
dc.contributor.authorPsaty, BMen_US
dc.contributor.authorLorentzon, Men_US
dc.contributor.authorForoud, Ten_US
dc.contributor.authorHarris, TBen_US
dc.contributor.authorHofman, Aen_US
dc.contributor.authorJansson, JOen_US
dc.contributor.authorCauley, JAen_US
dc.contributor.authorUitterlinden, AGen_US
dc.contributor.authorGibson, Qen_US
dc.contributor.authorJärvelin, MRen_US
dc.contributor.authorKarasik, Den_US
dc.contributor.authorSiscovick, DSen_US
dc.contributor.authorEcons, MJen_US
dc.contributor.authorKritchevsky, SBen_US
dc.contributor.authorFlorez, JCen_US
dc.contributor.authorTodd, JAen_US
dc.contributor.authorDupuis, Jen_US
dc.contributor.authorHyppönen, Een_US
dc.contributor.authorSpector, TDen_US
dc.date.accessioned2013-05-27T07:12:09Z-
dc.date.available2013-05-27T07:12:09Z-
dc.date.issued2010en_US
dc.identifier.citationThe Lancet, 2010, v. 376 n. 9736, p. 180-188en_US
dc.identifier.issn0140-6736en_US
dc.identifier.urihttp://hdl.handle.net/10722/183386-
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. Funding Full funding sources listed at end of paper (see Acknowledgments). ].en_US
dc.languageengen_US
dc.publisherThe Lancet Publishing Group. The Journal's web site is located at http://www.elsevier.com/locate/lanceten_US
dc.relation.ispartofThe Lanceten_US
dc.subject.meshCanadaen_US
dc.subject.meshChromosomes, Human, Pair 11en_US
dc.subject.meshChromosomes, Human, Pair 4en_US
dc.subject.meshCohort Studiesen_US
dc.subject.meshDietary Supplementsen_US
dc.subject.meshEuropeen_US
dc.subject.meshEuropean Continental Ancestry Group - Geneticsen_US
dc.subject.meshGenetic Predisposition To Diseaseen_US
dc.subject.meshGenome-Wide Association Studyen_US
dc.subject.meshHeterozygoteen_US
dc.subject.meshHomozygoteen_US
dc.subject.meshHumansen_US
dc.subject.meshImmunoassayen_US
dc.subject.meshInternational Cooperationen_US
dc.subject.meshLinkage Disequilibriumen_US
dc.subject.meshPolymorphism, Single Nucleotideen_US
dc.subject.meshSeasonsen_US
dc.subject.meshUnited Statesen_US
dc.subject.meshVitamin D - Analogs & Derivatives - Blood - Geneticsen_US
dc.subject.meshVitamin D Deficiency - Blood - Genetics - Prevention & Controlen_US
dc.titleCommon genetic determinants of vitamin D insufficiency: A genome-wide association studyen_US
dc.typeArticleen_US
dc.identifier.emailReid, DM: lung1212@hku.hken_US
dc.identifier.authorityReid, DM=rp01749en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1016/S0140-6736(10)60588-0en_US
dc.identifier.pmid20541252-
dc.identifier.scopuseid_2-s2.0-77955052903en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77955052903&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume376en_US
dc.identifier.issue9736en_US
dc.identifier.spage180en_US
dc.identifier.epage188en_US
dc.identifier.isiWOS:000280313100025-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.f10004324982-
dc.identifier.scopusauthoridWang, TJ=7405565318en_US
dc.identifier.scopusauthoridZhang, F=7404968786en_US
dc.identifier.scopusauthoridRichards, JB=14051143300en_US
dc.identifier.scopusauthoridKestenbaum, B=35482488400en_US
dc.identifier.scopusauthoridVan Meurs, JB=7005539448en_US
dc.identifier.scopusauthoridBerry, D=55077176000en_US
dc.identifier.scopusauthoridKiel, DP=7005526959en_US
dc.identifier.scopusauthoridStreeten, EA=6601987607en_US
dc.identifier.scopusauthoridOhlsson, C=7006582588en_US
dc.identifier.scopusauthoridKoller, DL=35399194400en_US
dc.identifier.scopusauthoridPeltonen, L=36051313500en_US
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dc.identifier.scopusauthoridO'Reilly, PF=24504286800en_US
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dc.identifier.scopusauthoridGlazer, NL=8509316100en_US
dc.identifier.scopusauthoridVandenput, L=8782798800en_US
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