Article: Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass

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TitleMeta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass
AuthorsIoannidis, JPA12 18 19
Ng, MY10
Sham, PC1 10
Zintzaras, E23
Lewis, CM1
Deng, HW9 20 21
Econs, MJ6
Karasik, D7
Devoto, M16
Kammerer, CM17
Spector, T8
Andrew, T8
Cupples, LA14
Duncan, EL2
Foroud, T6
Kiel, DP7
Koller, D6
Langdahl, B22
Mitchell, BD5
Peacock, M6
Recker, R9
Shen, H20
SolChurch, K13
Spotila, LD15
Uitterlinden, AG4
Wilson, SG3
Kung, AWC10
Ralston, SH11
KeywordsBMD
Genome scan
Genome search
Linkage
Meta-analysis
Osteoporosis
Issue Date2007
PublisherAmerican Society for Bone and Mineral Research. The Journal's web site is located at http://www.jbmr.org/view/0/index.html
CitationJournal Of Bone And Mineral Research, 2007, v. 22 n. 2, p. 173-183 [How to Cite?]
DOI: http://dx.doi.org/10.1359/jbmr.060806
AbstractSeveral genome-wide scans have been performed to detect loci that regulate BMD, but these have yielded inconsistent results, with limited replication of linkage peaks in different studies. In an effort to improve statistical power for detection of these loci, we performed a meta-analysis of genome-wide scans in which spine or hip BMD were studied. Evidence was gained to suggest that several chromosomal loci regulate BMD in a site-specific and sex-specific manner. Introduction: BMD is a heritable trait and an important predictor of osteoporotic fracture risk. Several genome-wide scans have been performed in an attempt to detect loci that regulate BMD, but there has been limited replication of linkage peaks between studies. In an attempt to resolve these inconsistencies, we conducted a collaborative meta-analysis of genome-wide linkage scans in which femoral neck BMD (FN-BMD) or lumbar spine BMD (LS-BMD) had been studied. Materials and Methods: Data were accumulated from nine genome-wide scans involving 11,842 subjects. Data were analyzed separately for LS-BMD and FN-BMD and by sex. For each study, genomic bins of 30 cM were defined and ranked according to the maximum LOD score they contained. While various densitometers were used in different studies, the ranking approach that we used means that the results are not confounded by the fact that different measurement devices were used. Significance for high average rank and heterogeneity was obtained through Monte Carlo testing. Results: For LS-BMD, the quantitative trait locus (QTL) with greatest significance was on chromosome 1p13.3-q23.3 (p = 0.004), but this exhibited high heterogeneity and the effect was specific for women. Other significant LS-BMD QTLs were on chromosomes 12q24.31-qter, 3p25.3-p22.1, 11p12-q13.3, and 1q32-q42.3, including one on 18p11-q12.3 that had not been detected by individual studies. For FN-BMD, the strongest QTL was on chromosome 9q31.1-q33.3 (p = 0.002). Other significant QTLs were identified on chromosomes 17p12-q21.33, 14q13.1-q24.1, 9q21.32-q31.1, and 5q14.3-q23.2. There was no correlation in average ranks of bins between men and women and the loci that regulated BMD in men and women and at different sites were largely distinct. Conclusions: This large-scale meta-analysis provided evidence for replication of several QTLs identified in previous studies and also identified a QTL on chromosome 18p11-q12.3, which had not been detected by individual studies. However, despite the large sample size, none of the individual loci identified reached genome-wide significance. © 2007 American Society for Bone and Mineral Research.
ISSN0884-0431
2011 Impact Factor: 6.373
2011 SCImago Journal Rankings: 0.622
DOIhttp://dx.doi.org/10.1359/jbmr.060806
ISI Accession Number IDWOS:000243668800001
ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorIoannidis, JPA
dc.contributor.authorNg, MY
dc.contributor.authorSham, PC
dc.contributor.authorZintzaras, E
dc.contributor.authorLewis, CM
dc.contributor.authorDeng, HW
dc.contributor.authorEcons, MJ
dc.contributor.authorKarasik, D
dc.contributor.authorDevoto, M
dc.contributor.authorKammerer, CM
dc.contributor.authorSpector, T
dc.contributor.authorAndrew, T
dc.contributor.authorCupples, LA
dc.contributor.authorDuncan, EL
dc.contributor.authorForoud, T
dc.contributor.authorKiel, DP
dc.contributor.authorKoller, D
dc.contributor.authorLangdahl, B
dc.contributor.authorMitchell, BD
dc.contributor.authorPeacock, M
dc.contributor.authorRecker, R
dc.contributor.authorShen, H
dc.contributor.authorSolChurch, K
dc.contributor.authorSpotila, LD
dc.contributor.authorUitterlinden, AG
dc.contributor.authorWilson, SG
dc.contributor.authorKung, AWC
dc.contributor.authorRalston, SH
dc.date.accessioned2010-09-06T07:34:48Z
dc.date.available2010-09-06T07:34:48Z
dc.date.issued2007
dc.description.abstractSeveral genome-wide scans have been performed to detect loci that regulate BMD, but these have yielded inconsistent results, with limited replication of linkage peaks in different studies. In an effort to improve statistical power for detection of these loci, we performed a meta-analysis of genome-wide scans in which spine or hip BMD were studied. Evidence was gained to suggest that several chromosomal loci regulate BMD in a site-specific and sex-specific manner. Introduction: BMD is a heritable trait and an important predictor of osteoporotic fracture risk. Several genome-wide scans have been performed in an attempt to detect loci that regulate BMD, but there has been limited replication of linkage peaks between studies. In an attempt to resolve these inconsistencies, we conducted a collaborative meta-analysis of genome-wide linkage scans in which femoral neck BMD (FN-BMD) or lumbar spine BMD (LS-BMD) had been studied. Materials and Methods: Data were accumulated from nine genome-wide scans involving 11,842 subjects. Data were analyzed separately for LS-BMD and FN-BMD and by sex. For each study, genomic bins of 30 cM were defined and ranked according to the maximum LOD score they contained. While various densitometers were used in different studies, the ranking approach that we used means that the results are not confounded by the fact that different measurement devices were used. Significance for high average rank and heterogeneity was obtained through Monte Carlo testing. Results: For LS-BMD, the quantitative trait locus (QTL) with greatest significance was on chromosome 1p13.3-q23.3 (p = 0.004), but this exhibited high heterogeneity and the effect was specific for women. Other significant LS-BMD QTLs were on chromosomes 12q24.31-qter, 3p25.3-p22.1, 11p12-q13.3, and 1q32-q42.3, including one on 18p11-q12.3 that had not been detected by individual studies. For FN-BMD, the strongest QTL was on chromosome 9q31.1-q33.3 (p = 0.002). Other significant QTLs were identified on chromosomes 17p12-q21.33, 14q13.1-q24.1, 9q21.32-q31.1, and 5q14.3-q23.2. There was no correlation in average ranks of bins between men and women and the loci that regulated BMD in men and women and at different sites were largely distinct. Conclusions: This large-scale meta-analysis provided evidence for replication of several QTLs identified in previous studies and also identified a QTL on chromosome 18p11-q12.3, which had not been detected by individual studies. However, despite the large sample size, none of the individual loci identified reached genome-wide significance. © 2007 American Society for Bone and Mineral Research.
dc.description.natureLink_to_subscribed_fulltext
dc.identifier.citationJournal Of Bone And Mineral Research, 2007, v. 22 n. 2, p. 173-183 [How to Cite?]
DOI: http://dx.doi.org/10.1359/jbmr.060806
dc.identifier.doihttp://dx.doi.org/10.1359/jbmr.060806
dc.identifier.epage183
dc.identifier.hkuros131069
dc.identifier.isiWOS:000243668800001
dc.identifier.issn0884-0431
2011 Impact Factor: 6.373
2011 SCImago Journal Rankings: 0.622
dc.identifier.issue2
dc.identifier.openurl
dc.identifier.pmid17228994
dc.identifier.scopuseid_2-s2.0-33846473055
dc.identifier.spage173
dc.identifier.urihttp://hdl.handle.net/10722/77703
dc.identifier.volume22
dc.languageeng
dc.publisherAmerican Society for Bone and Mineral Research. The Journal's web site is located at http://www.jbmr.org/view/0/index.html
dc.publisher.placeUnited States
dc.relation.ispartofJournal of Bone and Mineral Research
dc.relation.referencesReferences in Scopus
dc.subject.meshBone Density - genetics
dc.subject.meshChromosome Mapping
dc.subject.meshFemale
dc.subject.meshGenetic Linkage
dc.subject.meshGenome, Human
dc.subject.meshHumans
dc.subject.meshMale
dc.subject.meshQuantitative Trait Loci
dc.subject.meshSex Factors
dc.subjectBMD
dc.subjectGenome scan
dc.subjectGenome search
dc.subjectLinkage
dc.subjectMeta-analysis
dc.subjectOsteoporosis
dc.titleMeta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass
dc.typeArticle
Author Affiliations
  1. King's College London
  2. Churchill Hospital
  3. Sir Charles Gairdner Hospital
  4. Erasmus University Medical Center
  5. University of Maryland School of Medicine
  6. Indiana University School of Medicine Indianapolis
  7. Harvard Medical School
  8. St Thomas' Hospital
  9. Creighton University School of Medicine
  10. The University of Hong Kong
  11. Western General Hospital
  12. Tufts University School of Medicine
  13. Nemours
  14. Boston University School of Public Health
  15. ScienceScribe
  16. CHOP
  17. University of Pittsburgh
  18. Foundation for Research and Technology-Hellas
  19. University of Ioannina, School of Medicine
  20. University of Missouri-Kansas City
  21. Hunan Normal University
  22. Ârhus Universitetshospital
  23. Panepistimio Thesalias