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Published in: Osteoporosis International 12/2018

01-12-2018 | Original Article

Gene-based GWAS analysis for consecutive studies of GEFOS

Authors: W. Zhu, C. Xu, J.-G. Zhang, H. He, K.-H. Wu, L. Zhang, Y. Zeng, Y. Zhou, K.-J. Su, H.-W. Deng

Published in: Osteoporosis International | Issue 12/2018

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Abstract

Summary

By integrating the multilevel biological evidence and bioinformatics analyses, the present study represents a systemic endeavor to identify BMD-associated genes and their roles in skeletal metabolism.

Introduction

Single-nucleotide polymorphism (SNP)-based genome-wide association studies (GWASs) have already identified about 100 loci associated with bone mineral density (BMD), but these loci only explain a small proportion of heritability to osteoporosis risk. In the present study, we performed a gene-based analysis of the largest GWASs in the bone field to identify additional BMD-associated genes.

Methods

BMD-associated genes were identified by combining the summary statistic P values of SNPs across individual genes in the two consecutive meta-analyses of GWASs from the Genetic Factors for Osteoporosis (GEFOS) studies. The potential functionality of these genes to bone was partially assessed by differential gene expression analysis. Additionally, the consistency of the identification of potential bone mineral density (BMD)-associated variants were evaluated by estimating the correlation of the P values of the same single-nucleotide polymorphisms (SNPs)/genes between the two consecutive Genetic Factors for Osteoporosis Studies (GEFOS) with largely overlapping samples.

Results

Compared to the SNP-based analysis, the gene-based strategy identified additional BMD-associated genes with genome-wide significance and increased their mutual replication between the two GEFOS datasets. Among these BMD-associated genes, three novel genes (UBTF, AAAS, and C11orf58) were partially validated at the gene expression level. The correlation analysis presented a moderately high between-study consistency of potential BMD-associated variants.

Conclusions

Gene-based analysis as a supplementary strategy to SNP-based genome-wide association studies, when applied here, is shown that it helped identify some novel BMD-associated genes. In addition to its empirically increased statistical power, gene-based analysis also provides a higher testing stability for identification of BMD genes.
Appendix
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Metadata
Title
Gene-based GWAS analysis for consecutive studies of GEFOS
Authors
W. Zhu
C. Xu
J.-G. Zhang
H. He
K.-H. Wu
L. Zhang
Y. Zeng
Y. Zhou
K.-J. Su
H.-W. Deng
Publication date
01-12-2018
Publisher
Springer London
Published in
Osteoporosis International / Issue 12/2018
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI
https://doi.org/10.1007/s00198-018-4654-y

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