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Article: Association of JAG1 with Bone Mineral Density and Osteoporotic Fractures: A Genome-wide Association Study and Follow-up Replication Studies

TitleAssociation of JAG1 with Bone Mineral Density and Osteoporotic Fractures: A Genome-wide Association Study and Follow-up Replication Studies
Authors
Issue Date2010
PublisherCell Press. The Journal's web site is located at http://www.cell.com/AJHG/
Citation
American Journal Of Human Genetics, 2010, v. 86 n. 2, p. 229-239 How to Cite?
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 × 10 -8 for lumbar spine [LS] and p = 4.15 × 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 × 10 -9 for LS and 3.47 × 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. © 2010 The American Society of Human Genetics.
Persistent Identifierhttp://hdl.handle.net/10722/65609
ISSN
2014 Impact Factor: 10.931
2014 SCImago Journal Rankings: 7.223
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Hong Kong Research Grant Council
HKU Foundation
Matching Grant
CRCG
The University of Hong Kong
Wellcome Trust
European Community's Sixth and Seventh Framework ProgrammesFP7/2007-2013
ENGAGEHEALTH-F4-2007-201413
1711-5 GenomEUtwin ProjectQLG2-CT-2002-01254
Department of Health via the National Institute for Health Research (NIHR)
Biotechnology and Biological Sciences Research Council (BBSRC)G20234
National Eye Institute via an NIH/CIDR
US National Institute for Arthritis, Musculoskeletal and Skin Diseases
National Institute on AgingR01 AR/AG 41398
R01 AR 050066
National Heart, Lung, and Blood Institute's Framingham Heart StudyN01-HC-25195
Affymetrix, Inc.N02-HL-6-4278
Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine
Boston Medical Center
Funding Information:

This project is supported by Hong Kong Research Grant Council; The Bone Health Fund of HKU Foundation; and Matching Grant, CRCG Grant, and The Osteoporosis Research Fund of The University of Hong Kong. The Twins UK Study was funded by the Wellcome Trust, European Community's Sixth and Seventh Framework Programmes (FP7/2007-2013), ENGAGE project HEALTH-F4-2007-201413, and the 1711-5 GenomEUtwin Project (QLG2-CT-2002-01254). The study also receives Support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & StThornas' NHS Foundation Trust in partnership with King's College London. T.D.S. is an NIHR senior Investigator. The project also received support from a Biotechnology and Biological Sciences Research Council (BBSRC) project grant (G20234). The authors acknowledge the funding and support of the National Eye Institute via an NIH/CIDR genotyping project (PI, Terri Young). For genotyping of the Twins UK study, we thank the staff from the Genotyping Facilities at the Wellcome Trust Sanger Institute for sample preparation, Quality Control and Genotyping led by Leena Peltonen and Panos Deloukas; Le Centre National de Genotypage, France, led by Mark Lathrop; Duke University, North Carolina, USA, led by David Goldstein; and the Finnish Institute of Molecular Medicine, Finnish Genome Center, University of Helsinki, led by Aarno Palotie. The Framingham Osteoporosis Study (FOS) study was funded by grants from the US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute oil Aging (R01 AR/AG 41398 to D.P.K. and R01 AR 050066 to D.K.). The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted with the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. The following are employees of deCODE Company, Iceland, and own stock or stock options of deCODE Company: U.S., B.V.H., U.T., and K.S.

References

 

DC FieldValueLanguage
dc.contributor.authorKung, AWCen_HK
dc.contributor.authorXiao, SMen_HK
dc.contributor.authorCherny, Sen_HK
dc.contributor.authorLi, GHYen_HK
dc.contributor.authorGao, Yen_HK
dc.contributor.authorTso, Gen_HK
dc.contributor.authorLau, KSen_HK
dc.contributor.authorLuk, KDKen_HK
dc.contributor.authorLiu, Jmen_HK
dc.contributor.authorCui, Ben_HK
dc.contributor.authorZhang, MJen_HK
dc.contributor.authorZhang, Zlen_HK
dc.contributor.authorHe, Jwen_HK
dc.contributor.authorYue, Hen_HK
dc.contributor.authorXia, Wben_HK
dc.contributor.authorLuo, Lmen_HK
dc.contributor.authorHe, Slen_HK
dc.contributor.authorKiel, DPen_HK
dc.contributor.authorKarasik, Den_HK
dc.contributor.authorHsu, YHen_HK
dc.contributor.authorCupples, LAen_HK
dc.contributor.authorDemissie, Sen_HK
dc.contributor.authorStyrkarsdottir, Uen_HK
dc.contributor.authorHalldorsson, BVen_HK
dc.contributor.authorSigurdsson, Gen_HK
dc.contributor.authorThorsteinsdottir, Uen_HK
dc.contributor.authorStefansson, Ken_HK
dc.contributor.authorRichards, JBen_HK
dc.contributor.authorZhai, Gen_HK
dc.contributor.authorSoranzo, Nen_HK
dc.contributor.authorValdes, Aen_HK
dc.contributor.authorSpector, TDen_HK
dc.contributor.authorSham, PCen_HK
dc.date.accessioned2010-09-06T02:04:37Z-
dc.date.available2010-09-06T02:04:37Z-
dc.date.issued2010en_HK
dc.identifier.citationAmerican Journal Of Human Genetics, 2010, v. 86 n. 2, p. 229-239en_HK
dc.identifier.issn0002-9297en_HK
dc.identifier.urihttp://hdl.handle.net/10722/65609-
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 × 10 -8 for lumbar spine [LS] and p = 4.15 × 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 × 10 -9 for LS and 3.47 × 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. © 2010 The American Society of Human Genetics.en_HK
dc.languageeng-
dc.publisherCell Press. The Journal's web site is located at http://www.cell.com/AJHG/en_HK
dc.relation.ispartofAmerican Journal of Human Geneticsen_HK
dc.subject.meshBone Density - genetics-
dc.subject.meshCalcium-Binding Proteins - genetics-
dc.subject.meshFractures, Bone - complications - genetics - physiopathology-
dc.subject.meshGenetic Predisposition to Disease-
dc.subject.meshIntercellular Signaling Peptides and Proteins - genetics-
dc.titleAssociation of JAG1 with Bone Mineral Density and Osteoporotic Fractures: A Genome-wide Association Study and Follow-up Replication Studiesen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0002-9297&volume=86&issue=2&spage=229&epage=239&date=2010&atitle=Association+of+JAG1+with+bone+mineral+density+and+osteoporotic+fractures:+a+genome-wide+association+study+and+follow-up+replication+studies-
dc.identifier.emailKung, AWC: awckung@hku.hken_HK
dc.identifier.emailCherny, S: cherny@hku.hken_HK
dc.identifier.emailLuk, KDK: hcm21000@hku.hken_HK
dc.identifier.emailSham, PC: pcsham@hku.hken_HK
dc.identifier.authorityKung, AWC=rp00368en_HK
dc.identifier.authorityCherny, S=rp00232en_HK
dc.identifier.authorityLuk, KDK=rp00333en_HK
dc.identifier.authoritySham, PC=rp00459en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.ajhg.2009.12.014en_HK
dc.identifier.pmid20096396en_HK
dc.identifier.pmcidPMC2820171-
dc.identifier.scopuseid_2-s2.0-76249108602en_HK
dc.identifier.hkuros171281-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-76249108602&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume86en_HK
dc.identifier.issue2en_HK
dc.identifier.spage229en_HK
dc.identifier.epage239en_HK
dc.identifier.eissn1537-6605-
dc.identifier.isiWOS:000274637200012-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridKung, AWC=7102322339en_HK
dc.identifier.scopusauthoridXiao, SM=7402022586en_HK
dc.identifier.scopusauthoridCherny, S=7004670001en_HK
dc.identifier.scopusauthoridLi, GHY=35080710200en_HK
dc.identifier.scopusauthoridGao, Y=54792979500en_HK
dc.identifier.scopusauthoridTso, G=8617703000en_HK
dc.identifier.scopusauthoridLau, KS=35205833900en_HK
dc.identifier.scopusauthoridLuk, KDK=7201921573en_HK
dc.identifier.scopusauthoridLiu, Jm=27168787400en_HK
dc.identifier.scopusauthoridCui, B=7101621705en_HK
dc.identifier.scopusauthoridZhang, MJ=7601553697en_HK
dc.identifier.scopusauthoridZhang, Zl=34878137400en_HK
dc.identifier.scopusauthoridHe, Jw=35215101000en_HK
dc.identifier.scopusauthoridYue, H=35217253000en_HK
dc.identifier.scopusauthoridXia, Wb=35794570900en_HK
dc.identifier.scopusauthoridLuo, Lm=35794593800en_HK
dc.identifier.scopusauthoridHe, Sl=35794488400en_HK
dc.identifier.scopusauthoridKiel, DP=7005526959en_HK
dc.identifier.scopusauthoridKarasik, D=7004384589en_HK
dc.identifier.scopusauthoridHsu, YH=8071612400en_HK
dc.identifier.scopusauthoridCupples, LA=7007090535en_HK
dc.identifier.scopusauthoridDemissie, S=35292066400en_HK
dc.identifier.scopusauthoridStyrkarsdottir, U=12761328700en_HK
dc.identifier.scopusauthoridHalldorsson, BV=6603240812en_HK
dc.identifier.scopusauthoridSigurdsson, G=7005332253en_HK
dc.identifier.scopusauthoridThorsteinsdottir, U=6602988969en_HK
dc.identifier.scopusauthoridStefansson, K=7005997553en_HK
dc.identifier.scopusauthoridRichards, JB=14051143300en_HK
dc.identifier.scopusauthoridZhai, G=8983204600en_HK
dc.identifier.scopusauthoridSoranzo, N=6602345139en_HK
dc.identifier.scopusauthoridValdes, A=35427771900en_HK
dc.identifier.scopusauthoridSpector, TD=35351391300en_HK
dc.identifier.scopusauthoridSham, PC=34573429300en_HK
dc.identifier.citeulike9248801-

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