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Common variants in the region around Osterix are associated with bone mineral density and growth in childhood.

Timpson NJ, Tobias JH, Richards JB, Soranzo N, Duncan EL, Sims AM, Whittaker P, Kumanduri V, Zhai G, Glaser B, Eisman J, Jones G, Nicholson G, Prince R, Seeman E, Spector TD, Brown MA, Peltonen L, Smith GD, Deloukas P, Evans DM - Hum. Mol. Genet. (2009)

Bottom Line: We compared results with a scan of 134 adults with high or low hip BMD.Moreover, all SNPs were related to height in ALSPAC children, but not weight or body mass index, and when height was included as a covariate in the regression equation, the association with total body BMD was attenuated.We conclude that genetic variants in the region of Osterix are associated with BMD in children and adults probably through primary effects on growth.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Bristol, UK.

ABSTRACT
Peak bone mass achieved in adolescence is a determinant of bone mass in later life. In order to identify genetic variants affecting bone mineral density (BMD), we performed a genome-wide association study of BMD and related traits in 1518 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). We compared results with a scan of 134 adults with high or low hip BMD. We identified associations with BMD in an area of chromosome 12 containing the Osterix (SP7) locus, a transcription factor responsible for regulating osteoblast differentiation (ALSPAC: P = 5.8 x 10(-4); Australia: P = 3.7 x 10(-4)). This region has previously shown evidence of association with adult hip and lumbar spine BMD in an Icelandic population, as well as nominal association in a UK population. A meta-analysis of these existing studies revealed strong association between SNPs in the Osterix region and adult lumbar spine BMD (P = 9.9 x 10(-11)). In light of these findings, we genotyped a further 3692 individuals from ALSPAC who had whole body BMD and confirmed the association in children as well (P = 5.4 x 10(-5)). Moreover, all SNPs were related to height in ALSPAC children, but not weight or body mass index, and when height was included as a covariate in the regression equation, the association with total body BMD was attenuated. We conclude that genetic variants in the region of Osterix are associated with BMD in children and adults probably through primary effects on growth.

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Related in: MedlinePlus

A graphical representation of the region on chromosome 12 that displays nominal association in both the ALSPAC and Australian genome-wide association scans. Gene tracks, location of SNPs (blue lines), linkage disequilibrium between markers and –log10 P-values for ALSPAC (upper) and Australian (bottom) genome scans are shown. The strongest signals occur in and around the genes Osterix and AAAS, although linkage disequilibrium is strong and extends across a wider region that includes the genes ESPL1, PFDN5 and MYG1.
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DDP052F1: A graphical representation of the region on chromosome 12 that displays nominal association in both the ALSPAC and Australian genome-wide association scans. Gene tracks, location of SNPs (blue lines), linkage disequilibrium between markers and –log10 P-values for ALSPAC (upper) and Australian (bottom) genome scans are shown. The strongest signals occur in and around the genes Osterix and AAAS, although linkage disequilibrium is strong and extends across a wider region that includes the genes ESPL1, PFDN5 and MYG1.

Mentions: Tables S1–S4 in the Supplementary Material display a full list of SNPs that exhibit nominal evidence of association (P < 10−4) with the bone phenotypes in the ALSPAC genome-wide association scan. While no SNP passed a stringent threshold required for genome-wide significance in the ALSPAC discovery set (0.05/315807=1.6 × 10−7), a number of SNPs in candidate genes displayed nominal associations with BMD, BMC, bone area and/or aBMC obtained from whole body DXA scans. These included the SNPs rs525735 (BMD: T = 3.16, P = 0.002; aBMC: T = 4.30, P = 1.9 × 10−5) and rs168568 (BMD: T = 3.48, P = 0.0005; BMC: T = 2.58, P = 0.01; aBMC: T = 3.07, P = 0.002) in the gene OSMR, the SNP rs1798802 (BMD: T = −3.18, P = 0.002; aBMC: T = −3.70, P = 0.0002) in the gene CTNNB1, and several SNPs residing in a linkage disequilibrium block near the gene Osterix (Fig. 1 and Table 2). In contrast, SNPs in or near RANKL (rs9594759, rs9594738), OPG (rs6993813, rs6469804), ZBTB40 (rs7524102, rs6696981), the MHC (rs3130340) and SNPs in or close to ESR1 (rs2504063, rs851982, rs9479055, rs4870044, rs1038304, rs6929137, rs1999805), which had previously displayed association with hip and spine BMD in a recent Icelandic genome-wide association study, did not show strong evidence of association in our study (P > 0.01 across all phenotypes). Similarly, we did not find any evidence of association for the SNP rs4355801 (near TNFRSF11B) which was recently identified in a European study of hip and spine BMD involving 8557 participants (9), although we did find some evidence of association between rs3736228 (in LRP5) and BMD in the same direction as reported by Richards et al. (9) (P = 0.017).


Common variants in the region around Osterix are associated with bone mineral density and growth in childhood.

Timpson NJ, Tobias JH, Richards JB, Soranzo N, Duncan EL, Sims AM, Whittaker P, Kumanduri V, Zhai G, Glaser B, Eisman J, Jones G, Nicholson G, Prince R, Seeman E, Spector TD, Brown MA, Peltonen L, Smith GD, Deloukas P, Evans DM - Hum. Mol. Genet. (2009)

A graphical representation of the region on chromosome 12 that displays nominal association in both the ALSPAC and Australian genome-wide association scans. Gene tracks, location of SNPs (blue lines), linkage disequilibrium between markers and –log10 P-values for ALSPAC (upper) and Australian (bottom) genome scans are shown. The strongest signals occur in and around the genes Osterix and AAAS, although linkage disequilibrium is strong and extends across a wider region that includes the genes ESPL1, PFDN5 and MYG1.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2664147&req=5

DDP052F1: A graphical representation of the region on chromosome 12 that displays nominal association in both the ALSPAC and Australian genome-wide association scans. Gene tracks, location of SNPs (blue lines), linkage disequilibrium between markers and –log10 P-values for ALSPAC (upper) and Australian (bottom) genome scans are shown. The strongest signals occur in and around the genes Osterix and AAAS, although linkage disequilibrium is strong and extends across a wider region that includes the genes ESPL1, PFDN5 and MYG1.
Mentions: Tables S1–S4 in the Supplementary Material display a full list of SNPs that exhibit nominal evidence of association (P < 10−4) with the bone phenotypes in the ALSPAC genome-wide association scan. While no SNP passed a stringent threshold required for genome-wide significance in the ALSPAC discovery set (0.05/315807=1.6 × 10−7), a number of SNPs in candidate genes displayed nominal associations with BMD, BMC, bone area and/or aBMC obtained from whole body DXA scans. These included the SNPs rs525735 (BMD: T = 3.16, P = 0.002; aBMC: T = 4.30, P = 1.9 × 10−5) and rs168568 (BMD: T = 3.48, P = 0.0005; BMC: T = 2.58, P = 0.01; aBMC: T = 3.07, P = 0.002) in the gene OSMR, the SNP rs1798802 (BMD: T = −3.18, P = 0.002; aBMC: T = −3.70, P = 0.0002) in the gene CTNNB1, and several SNPs residing in a linkage disequilibrium block near the gene Osterix (Fig. 1 and Table 2). In contrast, SNPs in or near RANKL (rs9594759, rs9594738), OPG (rs6993813, rs6469804), ZBTB40 (rs7524102, rs6696981), the MHC (rs3130340) and SNPs in or close to ESR1 (rs2504063, rs851982, rs9479055, rs4870044, rs1038304, rs6929137, rs1999805), which had previously displayed association with hip and spine BMD in a recent Icelandic genome-wide association study, did not show strong evidence of association in our study (P > 0.01 across all phenotypes). Similarly, we did not find any evidence of association for the SNP rs4355801 (near TNFRSF11B) which was recently identified in a European study of hip and spine BMD involving 8557 participants (9), although we did find some evidence of association between rs3736228 (in LRP5) and BMD in the same direction as reported by Richards et al. (9) (P = 0.017).

Bottom Line: We compared results with a scan of 134 adults with high or low hip BMD.Moreover, all SNPs were related to height in ALSPAC children, but not weight or body mass index, and when height was included as a covariate in the regression equation, the association with total body BMD was attenuated.We conclude that genetic variants in the region of Osterix are associated with BMD in children and adults probably through primary effects on growth.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Bristol, UK.

ABSTRACT
Peak bone mass achieved in adolescence is a determinant of bone mass in later life. In order to identify genetic variants affecting bone mineral density (BMD), we performed a genome-wide association study of BMD and related traits in 1518 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). We compared results with a scan of 134 adults with high or low hip BMD. We identified associations with BMD in an area of chromosome 12 containing the Osterix (SP7) locus, a transcription factor responsible for regulating osteoblast differentiation (ALSPAC: P = 5.8 x 10(-4); Australia: P = 3.7 x 10(-4)). This region has previously shown evidence of association with adult hip and lumbar spine BMD in an Icelandic population, as well as nominal association in a UK population. A meta-analysis of these existing studies revealed strong association between SNPs in the Osterix region and adult lumbar spine BMD (P = 9.9 x 10(-11)). In light of these findings, we genotyped a further 3692 individuals from ALSPAC who had whole body BMD and confirmed the association in children as well (P = 5.4 x 10(-5)). Moreover, all SNPs were related to height in ALSPAC children, but not weight or body mass index, and when height was included as a covariate in the regression equation, the association with total body BMD was attenuated. We conclude that genetic variants in the region of Osterix are associated with BMD in children and adults probably through primary effects on growth.

Show MeSH
Related in: MedlinePlus