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

John P A Ioannidis, Mandy Y. Ng, Pak C. Sham, Elias Zintzaras, Cathryn M. Lewis, Hong Wen Deng, Michael J. Econs, David Karasik, Marcella Devoto, Candace M. Kammerer, Tim Spector, Toby Andrew, L. Adrienne Cupples, Emma L. Duncan, Tatiana Foroud, Douglas P. Kiel, Daniel Koller, Bente Langdahl, Braxton D. Mitchell, Munro Peacock & 8 others Robert R. Recker, Hui Shen, Katia Sol-Church, Loretta D. Spotila, Andre G. Uitterlinden, Scott G. Wilson, Annie W C Kung, Stuart H. Ralston

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129 Citations (Scopus)

Abstract

Several 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.

Original languageEnglish
Pages (from-to)173-183
Number of pages11
JournalJournal of Bone and Mineral Research
Volume22
Issue number2
DOIs
StatePublished - Feb 2007

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Meta-Analysis
Genome
Spine
Bone and Bones
Chromosomes
Quantitative Trait Loci
Femur Neck
Osteoporotic Fractures
Sample Size
Hip
Equipment and Supplies

All Science Journal Classification (ASJC) codes

  • Surgery

Cite this

Ioannidis, J. P. A., Ng, M. Y., Sham, P. C., Zintzaras, E., Lewis, C. M., Deng, H. W., ... Ralston, S. H. (2007). Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass. Journal of Bone and Mineral Research, 22(2), 173-183. https://doi.org/10.1359/jbmr.060806

Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass. / Ioannidis, John P A; Ng, Mandy Y.; Sham, Pak C.; Zintzaras, Elias; Lewis, Cathryn M.; Deng, Hong Wen; Econs, Michael J.; Karasik, David; Devoto, Marcella; Kammerer, Candace M.; Spector, Tim; Andrew, Toby; Cupples, L. Adrienne; Duncan, Emma L.; Foroud, Tatiana; Kiel, Douglas P.; Koller, Daniel; Langdahl, Bente; Mitchell, Braxton D.; Peacock, Munro; Recker, Robert R.; Shen, Hui; Sol-Church, Katia; Spotila, Loretta D.; Uitterlinden, Andre G.; Wilson, Scott G.; Kung, Annie W C; Ralston, Stuart H.

In: Journal of Bone and Mineral Research, Vol. 22, No. 2, 02.2007, p. 173-183.

Research output: Contribution to journalArticle

Ioannidis, JPA, Ng, MY, Sham, PC, Zintzaras, E, Lewis, CM, Deng, HW, Econs, MJ, Karasik, D, Devoto, M, Kammerer, CM, Spector, T, Andrew, T, Cupples, LA, Duncan, EL, Foroud, T, Kiel, DP, Koller, D, Langdahl, B, Mitchell, BD, Peacock, M, Recker, RR, Shen, H, Sol-Church, K, Spotila, LD, Uitterlinden, AG, Wilson, SG, Kung, AWC & Ralston, SH 2007, 'Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass', Journal of Bone and Mineral Research, vol. 22, no. 2, pp. 173-183. https://doi.org/10.1359/jbmr.060806
Ioannidis, John P A ; Ng, Mandy Y. ; Sham, Pak C. ; Zintzaras, Elias ; Lewis, Cathryn M. ; Deng, Hong Wen ; Econs, Michael J. ; Karasik, David ; Devoto, Marcella ; Kammerer, Candace M. ; Spector, Tim ; Andrew, Toby ; Cupples, L. Adrienne ; Duncan, Emma L. ; Foroud, Tatiana ; Kiel, Douglas P. ; Koller, Daniel ; Langdahl, Bente ; Mitchell, Braxton D. ; Peacock, Munro ; Recker, Robert R. ; Shen, Hui ; Sol-Church, Katia ; Spotila, Loretta D. ; Uitterlinden, Andre G. ; Wilson, Scott G. ; Kung, Annie W C ; Ralston, Stuart H. / Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass. In: Journal of Bone and Mineral Research. 2007 ; Vol. 22, No. 2. pp. 173-183.
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abstract = "Several 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.",
author = "Ioannidis, {John P A} and Ng, {Mandy Y.} and Sham, {Pak C.} and Elias Zintzaras and Lewis, {Cathryn M.} and Deng, {Hong Wen} and Econs, {Michael J.} and David Karasik and Marcella Devoto and Kammerer, {Candace M.} and Tim Spector and Toby Andrew and Cupples, {L. Adrienne} and Duncan, {Emma L.} and Tatiana Foroud and Kiel, {Douglas P.} and Daniel Koller and Bente Langdahl and Mitchell, {Braxton D.} and Munro Peacock and Recker, {Robert R.} and Hui Shen and Katia Sol-Church and Spotila, {Loretta D.} and Uitterlinden, {Andre G.} and Wilson, {Scott G.} and Kung, {Annie W C} and Ralston, {Stuart H.}",
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TY - JOUR

T1 - Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass

AU - Ioannidis, John P A

AU - Ng, Mandy Y.

AU - Sham, Pak C.

AU - Zintzaras, Elias

AU - Lewis, Cathryn M.

AU - Deng, Hong Wen

AU - Econs, Michael J.

AU - Karasik, David

AU - Devoto, Marcella

AU - Kammerer, Candace M.

AU - Spector, Tim

AU - Andrew, Toby

AU - Cupples, L. Adrienne

AU - Duncan, Emma L.

AU - Foroud, Tatiana

AU - Kiel, Douglas P.

AU - Koller, Daniel

AU - Langdahl, Bente

AU - Mitchell, Braxton D.

AU - Peacock, Munro

AU - Recker, Robert R.

AU - Shen, Hui

AU - Sol-Church, Katia

AU - Spotila, Loretta D.

AU - Uitterlinden, Andre G.

AU - Wilson, Scott G.

AU - Kung, Annie W C

AU - Ralston, Stuart H.

PY - 2007/2

Y1 - 2007/2

N2 - Several 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.

AB - Several 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.

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