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dc.contributor.authorKung, Annie W C
dc.contributor.authorXiao, Su-Mei
dc.contributor.authorCherny, Stacey
dc.contributor.authorLi, Gloria H Y
dc.contributor.authorGao, Yi
dc.contributor.authorTso, Gloria
dc.contributor.authorLau, Kam S
dc.contributor.authorLuk, Keith D K
dc.contributor.authorLiu, Jian-min
dc.contributor.authorCui, Bin
dc.contributor.authorZhang, Min-Jia
dc.contributor.authorZhang, Zhen-lin
dc.contributor.authorHe, Jin-wei
dc.contributor.authorYue, Hua
dc.contributor.authorXia, Wia-bo
dc.contributor.authorLuo, Lian-mei
dc.contributor.authorHe, Shu-li
dc.contributor.authorKiel, Douglas P
dc.contributor.authorKarasik, David
dc.contributor.authorHsu, Yi-Hsiang
dc.contributor.authorCupples, L Adrienne
dc.contributor.authorDemissie, Serkalem
dc.contributor.authorStyrkarsdottir, Unnur
dc.contributor.authorHalldorsson, Bjarni V
dc.contributor.authorSigurdsson, Gunnar
dc.contributor.authorThorsteinsdottir, Unnur
dc.contributor.authorStefansson, Kari
dc.contributor.authorRichards, J Brent
dc.contributor.authorZhai, Guangju
dc.contributor.authorSoranzo, Nicole
dc.contributor.authorValdes, Ana
dc.contributor.authorSpector, Tim D
dc.contributor.authorSham, Pak C
dc.date.accessioned2010-06-15T14:05:05Z
dc.date.available2010-06-15T14:05:05Z
dc.date.issued2010-02-12
dc.date.submitted2010-06-15
dc.identifier.citationAm. J. Hum. Genet. 2010, 86(2):229-39en
dc.identifier.issn1537-6605
dc.identifier.pmid20096396
dc.identifier.doi10.1016/j.ajhg.2009.12.014
dc.identifier.urihttp://hdl.handle.net/2336/104872
dc.descriptionTo access publisher full text version of this article. Please click on the hyperlink in Additional Links fielden
dc.description.abstractBone mineral density (BMD), a diagnostic parameter for osteoporosis and a clinical predictor of fracture, is a polygenic trait with high heritability. To identify genetic variants that influence BMD in different ethnic groups, we performed a genome-wide association study (GWAS) on 800 unrelated Southern Chinese women with extreme BMD and carried out follow-up replication studies in six independent study populations of European descent and Asian populations including 18,098 subjects. In the meta-analysis, rs2273061 of the Jagged1 (JAG1) gene was associated with high BMD (p = 5.27 x 10(-8) for lumbar spine [LS] and p = 4.15 x 10(-5) for femoral neck [FN], n = 18,898). This SNP was further found to be associated with the low risk of osteoporotic fracture (p = 0.009, OR = 0.7, 95% CI 0.57-0.93, n = 1881). Region-wide and haplotype analysis showed that the strongest association evidence was from the linkage disequilibrium block 5, which included rs2273061 of the JAG1 gene (p = 8.52 x 10(-9) for LS and 3.47 x 10(-5) at FN). To assess the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of c-Myc to the "G" but not "A" allele of rs2273061. A mRNA expression study in both human bone-derived cells and peripheral blood mononuclear cells confirmed association of the high BMD-related allele G of rs2273061 with higher JAG1 expression. Our results identify the JAG1 gene as a candidate for BMD regulation in different ethnic groups, and it is a potential key factor for fracture pathogenesis.
dc.language.isoenen
dc.publisherUniversity of Chicago Pressen
dc.relation.urlhttp://dx.doi.org/10.1016/j.ajhg.2009.12.014en
dc.subject.meshAgeden
dc.subject.meshAllelesen
dc.subject.meshBone Densityen
dc.subject.meshCalcium-Binding Proteinsen
dc.subject.meshCohort Studiesen
dc.subject.meshElectrophoretic Mobility Shift Assayen
dc.subject.meshFemaleen
dc.subject.meshFollow-Up Studiesen
dc.subject.meshFractures, Boneen
dc.subject.meshGene Expression Regulationen
dc.subject.meshGenetic Predisposition to Diseaseen
dc.subject.meshGenome-Wide Association Studyen
dc.subject.meshHumansen
dc.subject.meshIntercellular Signaling Peptides and Proteinsen
dc.subject.meshMembrane Proteinsen
dc.subject.meshMiddle Ageden
dc.subject.meshOsteoporosisen
dc.subject.meshPolymorphism, Single Nucleotideen
dc.subject.meshReproducibility of Resultsen
dc.titleAssociation of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies.en
dc.typeArticleen
dc.contributor.departmentDepartment of Medicine, Research Centre of Heart, Brain, Hormone & Healthy Aging, Faculty of Medicine, The University of Hong Kong, Hong Kong, China. awckung@hkucc.hku.hken
dc.identifier.journalAmerican journal of human geneticsen
html.description.abstractBone mineral density (BMD), a diagnostic parameter for osteoporosis and a clinical predictor of fracture, is a polygenic trait with high heritability. To identify genetic variants that influence BMD in different ethnic groups, we performed a genome-wide association study (GWAS) on 800 unrelated Southern Chinese women with extreme BMD and carried out follow-up replication studies in six independent study populations of European descent and Asian populations including 18,098 subjects. In the meta-analysis, rs2273061 of the Jagged1 (JAG1) gene was associated with high BMD (p = 5.27 x 10(-8) for lumbar spine [LS] and p = 4.15 x 10(-5) for femoral neck [FN], n = 18,898). This SNP was further found to be associated with the low risk of osteoporotic fracture (p = 0.009, OR = 0.7, 95% CI 0.57-0.93, n = 1881). Region-wide and haplotype analysis showed that the strongest association evidence was from the linkage disequilibrium block 5, which included rs2273061 of the JAG1 gene (p = 8.52 x 10(-9) for LS and 3.47 x 10(-5) at FN). To assess the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of c-Myc to the "G" but not "A" allele of rs2273061. A mRNA expression study in both human bone-derived cells and peripheral blood mononuclear cells confirmed association of the high BMD-related allele G of rs2273061 with higher JAG1 expression. Our results identify the JAG1 gene as a candidate for BMD regulation in different ethnic groups, and it is a potential key factor for fracture pathogenesis.


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