Dataset Information

Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture.

ABSTRACT:

Background

Osteoporosis is a highly heritable trait. Many candidate genes have been proposed as being involved in regulating bone mineral density (BMD). Few of these findings have been replicated in independent studies.

Objective

To assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes.

Design

Large-scale meta-analysis of genome-wide association data.

Setting

5 international, multicenter, population-based studies.

Participants

Data on BMD were obtained from 19 195 participants (14 277 women) from 5 populations of European origin. Data on fracture were obtained from a prospective cohort (n = 5974) from the Netherlands.

Measurements

Systematic literature review using the Human Genome Epidemiology Navigator identified autosomal genes previously evaluated for association with osteoporosis. We explored the common SNPs arising from the haplotype map of the human genome (HapMap) across all these genes. BMD at the femoral neck and lumbar spine was measured by dual-energy x-ray absorptiometry. Fractures were defined as clinically apparent, site-specific, validated nonvertebral and vertebral low-energy fractures.

Results

150 candidate genes were identified and 36 016 SNPs in these loci were assessed. SNPs from 9 gene loci (ESR1, LRP4, ITGA1, LRP5, SOST, SPP1, TNFRSF11A, TNFRSF11B, and TNFSF11) were associated with BMD at either site. For most genes, no SNP was statistically significant. For statistically significant SNPs (n = 241), effect sizes ranged from 0.04 to 0.18 SD per allele. SNPs from the LRP5, SOST, SPP1, and TNFRSF11A loci were significantly associated with fracture risk; odds ratios ranged from 1.13 to 1.43 per allele. These effects on fracture were partially independent of BMD at SPP1 and SOST.

Limitation

Only common polymorphisms in linkage disequilibrium with SNPs in HapMap could be assessed, and previously reported associations for SNPs in some candidate genes could not be excluded.

Conclusion

In this large-scale collaborative genome-wide meta-analysis, 9 of 150 candidate genes were associated with regulation of BMD, 4 of which also significantly affected risk for fracture. However, most candidate genes had no consistent association with BMD.

SUBMITTER: Richards JB

PROVIDER: S-EPMC2842981 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Publications

Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture.

Richards J Brent JB Kavvoura Fotini K FK Rivadeneira Fernando F Styrkársdóttir Unnur U Estrada Karol K Halldórsson Bjarni V BV Hsu Yi-Hsiang YH Zillikens M Carola MC Wilson Scott G SG Mullin Benjamin H BH Amin Najaf N Aulchenko Yurii S YS Cupples L Adrienne LA Deloukas Panagiotis P Demissie Serkalem S Hofman Albert A Kong Augustine A Karasik David D van Meurs Joyce B JB Oostra Ben A BA Pols Huibert A P HA Sigurdsson Gunnar G Thorsteinsdottir Unnur U Soranzo Nicole N Williams Frances M K FM Zhou Yanhua Y Ralston Stuart H SH Thorleifsson Gudmar G van Duijn Cornelia M CM Kiel Douglas P DP Stefansson Kari K Uitterlinden André G AG Ioannidis John P A JP Spector Tim D TD

Annals of internal medicine 20091001 8

<h4>Background</h4>Osteoporosis is a highly heritable trait. Many candidate genes have been proposed as being involved in regulating bone mineral density (BMD). Few of these findings have been replicated in independent studies.<h4>Objective</h4>To assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes.<h4>Design</h4>Large-scale meta-analysis of genome-wide association data.<h4>Setting</h4>5 intern ...[more]

PMID: 19841454

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Project description:ObjectivesEvidence from observational studies suggested oral diseases (periodontitis (PD) and dental caries) may increase susceptibility to bone loss. However, inherent confounding of observational studies limits causal interpretation. We aimed to conduct Mendelian randomization (MR) analysis to estimate the causal effect of oral diseases on osteoporosis (OP), bone mineral density (BMD) and fracture risk.MethodsWe used summary-level GWAS meta-analysis data from the GLIDE consortium to identify 7 and 17 single-nucleotide polymorphisms (SNPs) for periodontitis and DMFS (the sum of Decayed, Missing, and Filled tooth Surfaces) as the instrumental variables. MR analyses of these instruments were performed on European individuals for the association with BMD of forearm, femoral neck and lumbar spine; and individuals from FinnGen consortium for OP, OP with pathological fracture, postmenopausal OP with pathological fracture, and site-specific fractures. We performed single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR) to simultaneously assess independent causal effects of PD and DMFS on different outcomes. The estimates were primarily derived using inverse variance weighted (IVW) methods. Sensitivity analyses included weighted median, MR-egger, and Leave-one-out test.ResultsIn MVMR, after adjusting for PD, DMFS has a positive causal effect osteoporosis (OR = 1.165, [95% CI 1.020 to 1.331, P = 0.025]) and postmenopausal OP with pathological fracture (OR = 1.422, [95% CI 1.027 to 1.969, P = 0.034]). However, these causal relationships were not observed in the single-variable Mendelian randomization (SVMR) analysis. The causal associations were robust in various sensitivity analyses.ConclusionsIn conclusion, dental caries causally increases the risk of OP and postmenopausal OP with pathological fracture, suggesting the existence of teeth-bone axis. Proactive osteoporosis screening in patients with severe dental caries may be warranted for clinical consideration.

Project description:ObjectivesIn order to screen the altered gene expression profile in peripheral blood mononuclear cells of patients with osteoporosis, we performed an integrated analysis of the online microarray studies of osteoporosis.MethodsWe searched the Gene Expression Omnibus (GEO) database for microarray studies of peripheral blood mononuclear cells in patients with osteoporosis. Subsequently, we integrated gene expression data sets from multiple microarray studies to obtain differentially expressed genes (DEGs) between patients with osteoporosis and normal controls. Gene function analysis was performed to uncover the functions of identified DEGs.ResultsA total of three microarray studies were selected for integrated analysis. In all, 1125 genes were found to be signiﬁcantly differentially expressed between osteoporosis patients and normal controls, with 373 upregulated and 752 downregulated genes. Positive regulation of the cellular amino metabolic process (gene ontology (GO): 0033240, false discovery rate (FDR) = 1.00E + 00) was significantly enriched under the GO category for biological processes, while for molecular functions, flavin adenine dinucleotide binding (GO: 0050660, FDR = 3.66E-01) and androgen receptor binding (GO: 0050681, FDR = 6.35E-01) were significantly enriched. DEGs were enriched in many osteoporosis-related signalling pathways, including those of mitogen-activated protein kinase (MAPK) and calcium. Protein-protein interaction (PPI) network analysis showed that the significant hub proteins contained ubiquitin specific peptidase 9, X-linked (Degree = 99), ubiquitin specific peptidase 19 (Degree = 57) and ubiquitin conjugating enzyme E2 B (Degree = 57).ConclusionAnalysis of gene function of identified differentially expressed genes may expand our understanding of fundamental mechanisms leading to osteoporosis. Moreover, significantly enriched pathways, such as MAPK and calcium, may involve in osteoporosis through osteoblastic differentiation and bone formation.Cite this article: J. J. Li, B. Q. Wang, Q. Fei, Y. Yang, D. Li. Identification of candidate genes in osteoporosis by integrated microarray analysis. Bone Joint Res 2016;5:594-601. DOI: 10.1302/2046-3758.512.BJR-2016-0073.R1.

Dataset Information

Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture.

Background

Objective

Design

Setting

Participants

Measurements

Results

Limitation

Conclusion

Publications

Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture.

Similar Datasets

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