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Published in: Osteoporosis International 12/2021

Open Access 01-12-2021 | Osteoporosis | Original Article

Integrating genome-wide association and transcriptome prediction model identifies novel target genes for osteoporosis

Authors: M. Zhu, P. Yin, F. Hu, J. Jiang, L. Yin, Y. Li, S. Wang

Published in: Osteoporosis International | Issue 12/2021

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Abstract

Summary

In this study, we integrated large-scale GWAS summary data and used the predicted transcriptome-wide association study method to discover novel genes associated with osteoporosis. We identified 204 candidate genes, which provide novel clues for understanding the genetic mechanism of osteoporosis and indicate potential therapeutic targets.

Introduction

Osteoporosis is a highly polygenetic disease characterized by low bone mass and deterioration of the bone microarchitecture. Our objective was to discover novel candidate genes associated with osteoporosis.

Methods

To identify potential causal genes of the associated loci, we investigated trait-gene expression associations using the transcriptome-wide association study (TWAS) method. This method directly imputes gene expression effects from genome-wide association study (GWAS) data using a statistical prediction model trained on GTEx reference transcriptome data. We then performed a colocalization analysis to evaluate the posterior probability of biological patterns: associations characterized by a single causal variant or multiple distinct causal variants. Finally, a functional enrichment analysis of gene sets was performed using the VarElect and CluePedia tools, which assess the causal relationships between genes and a disease and search for potential gene’s functional pathways. The osteoporosis-associated genes were further confirmed based on the differentially expressed genes profiled from mRNA expression data of bone tissue.

Results

Our analysis identified 204 candidate genes, including 154 genes that have been previously associated with osteoporosis, 50 genes that have not been previously discovered. A biological function analysis found that 20 of the candidate genes were directly associated with osteoporosis. Further analysis of multiple gene expression profiles showed that 15 genes were differentially expressed in patients with osteoporosis. Among these, SLC11A2, MAP2K5, NFATC4, and HSP90B1 were enriched in four pathways, namely, mineral absorption pathway, MAPK signaling pathway, Wnt signaling pathway, and PI3K-Akt signaling pathway, which indicates a causal relationship with the occurrence of osteoporosis.

Conclusions

We demonstrated that transcriptome fine-mapping identifies more osteoporosis-related genes and provides key insight into the development of novel targeted therapeutics for the treatment of osteoporosis.
Appendix
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Metadata
Title
Integrating genome-wide association and transcriptome prediction model identifies novel target genes for osteoporosis
Authors
M. Zhu
P. Yin
F. Hu
J. Jiang
L. Yin
Y. Li
S. Wang
Publication date
01-12-2021
Publisher
Springer London
Published in
Osteoporosis International / Issue 12/2021
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI
https://doi.org/10.1007/s00198-021-06024-z

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