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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
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TitleAssociation of JAG1 with Bone Mineral Density and Osteoporotic Fractures: A Genome-wide Association Study and Follow-up Replication Studies
 
AuthorsKung, AWC3
Xiao, SM3
Cherny, S3
Li, GHY3
Gao, Y3
Tso, G3
Lau, KS3
Luk, KDK3
Liu, Jm13
Cui, B13
Zhang, MJ13
Zhang, Zl5
He, Jw5
Yue, H5
Xia, Wb10
Luo, Lm10
He, Sl10
Kiel, DP4
Karasik, D4
Hsu, YH4
Cupples, LA6 7
Demissie, S6 7
Styrkarsdottir, U
Halldorsson, BV1
Sigurdsson, G8 11
Thorsteinsdottir, U8
Stefansson, K8
Richards, JB12 2
Zhai, G2
Soranzo, N2 9
Valdes, A2
Spector, TD2
Sham, PC3
 
Issue Date2010
 
PublisherCell Press. The Journal's web site is located at http://www.cell.com/AJHG/
 
CitationAmerican Journal Of Human Genetics, 2010, v. 86 n. 2, p. 229-239 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.ajhg.2009.12.014
 
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.
 
ISSN0002-9297
2013 Impact Factor: 10.987
 
DOIhttp://dx.doi.org/10.1016/j.ajhg.2009.12.014
 
PubMed Central IDPMC2820171
 
ISI Accession Number IDWOS:000274637200012
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.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorKung, AWC
 
dc.contributor.authorXiao, SM
 
dc.contributor.authorCherny, S
 
dc.contributor.authorLi, GHY
 
dc.contributor.authorGao, Y
 
dc.contributor.authorTso, G
 
dc.contributor.authorLau, KS
 
dc.contributor.authorLuk, KDK
 
dc.contributor.authorLiu, Jm
 
dc.contributor.authorCui, B
 
dc.contributor.authorZhang, MJ
 
dc.contributor.authorZhang, Zl
 
dc.contributor.authorHe, Jw
 
dc.contributor.authorYue, H
 
dc.contributor.authorXia, Wb
 
dc.contributor.authorLuo, Lm
 
dc.contributor.authorHe, Sl
 
dc.contributor.authorKiel, DP
 
dc.contributor.authorKarasik, D
 
dc.contributor.authorHsu, YH
 
dc.contributor.authorCupples, LA
 
dc.contributor.authorDemissie, S
 
dc.contributor.authorStyrkarsdottir, U
 
dc.contributor.authorHalldorsson, BV
 
dc.contributor.authorSigurdsson, G
 
dc.contributor.authorThorsteinsdottir, U
 
dc.contributor.authorStefansson, K
 
dc.contributor.authorRichards, JB
 
dc.contributor.authorZhai, G
 
dc.contributor.authorSoranzo, N
 
dc.contributor.authorValdes, A
 
dc.contributor.authorSpector, TD
 
dc.contributor.authorSham, PC
 
dc.date.accessioned2010-09-06T02:04:37Z
 
dc.date.available2010-09-06T02:04:37Z
 
dc.date.issued2010
 
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.
 
dc.description.naturelink_to_subscribed_fulltext
 
dc.identifier.citationAmerican Journal Of Human Genetics, 2010, v. 86 n. 2, p. 229-239 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.ajhg.2009.12.014
 
dc.identifier.citeulike9248801
 
dc.identifier.doihttp://dx.doi.org/10.1016/j.ajhg.2009.12.014
 
dc.identifier.eissn1537-6605
 
dc.identifier.epage239
 
dc.identifier.hkuros171281
 
dc.identifier.isiWOS:000274637200012
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.

 
dc.identifier.issn0002-9297
2013 Impact Factor: 10.987
 
dc.identifier.issue2
 
dc.identifier.openurl
 
dc.identifier.pmcidPMC2820171
 
dc.identifier.pmid20096396
 
dc.identifier.scopuseid_2-s2.0-76249108602
 
dc.identifier.spage229
 
dc.identifier.urihttp://hdl.handle.net/10722/65609
 
dc.identifier.volume86
 
dc.languageeng
 
dc.publisherCell Press. The Journal's web site is located at http://www.cell.com/AJHG/
 
dc.publisher.placeUnited States
 
dc.relation.ispartofAmerican Journal of Human Genetics
 
dc.relation.referencesReferences in Scopus
 
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 Studies
 
dc.typeArticle
 
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Author Affiliations
  1. Reykjavik University
  2. King's College London
  3. The University of Hong Kong
  4. Harvard Medical School
  5. Sixth People's Hospital
  6. Framingham Heart Study
  7. Boston University School of Public Health
  8. University of Iceland
  9. Wellcome Trust Sanger Institute
  10. Ministry of Health of People's Republic of China
  11. Landspitali University Hospital
  12. McGill University
  13. Shanghai Jiao Tong University School of Medicine