Dataset Information

Integrating Transcriptome-Wide Association Study and mRNA Expression Profiling Identifies Novel Genes Associated With Osteonecrosis of the Femoral Head.

ABSTRACT:

Objective

This study aims to identify novel candidate genes associated with osteonecrosis of the femoral head (ONFH).

Methods

A transcriptome-wide association study (TWAS) was performed by integrating the genome-wide association study dataset of osteonecrosis (ON) in the UK Biobank with pre-computed mRNA expression reference weights of muscle skeleton (MS) and blood. The ON-associated genes identified by TWAS were further subjected to gene ontology (GO) analysis by the DAVID tool. Finally, a trans-omics comparative analysis of TWAS and genome-wide mRNA expression profiling was conducted to identify the common genes and the GO terms shared by both DNA-level TWAS and mRNA-level expression profile for ONFH.

Results

TWAS totally identified 564 genes that were with P _TWAS value <0.05 for MS and blood, such as CBX1 (P _TWAS = 0.0001 for MS), SRPK2 (P _TWAS = 0.0002 for blood), and MYO5A (P _TWAS = 0.0005 for blood). After comparing the genes detected by TWAS with the differentially expressed genes identified by mRNA expression profiling, we detected 59 overlapped genes, such as STEAP4 [P _TWAS = 0.0270, FC (fold change)_mRNA = 7.03], RABEP1 (P _TWAS = 0.010, FC_mRNA = 2.22), and MORC3 (P _TWAS = 0.0053, FC_mRNA = 2.92). The GO analysis of TWAS-identified genes discovered 53 GO terms for ON. Further comparing the GO results of TWAS and mRNA expression profiling identified four overlapped GO terms, including cysteine-type endopeptidase activity (P _TWAS = 0.0006, P _mRNA = 0.0227), extracellular space (P _TWAS = 0.0342, P _mRNA = 0.0012), protein binding (P _TWAS = 0.0112, P _mRNA = 0.0106), and ATP binding (P _TWAS = 0.0464, P _mRNA = 0.0033).

Conclusion

Several ONFH-associated genes and GO terms were identified by integrating TWAS and mRNA expression profiling. It provides novel clues to reveal the pathogenesis of ONFH.

SUBMITTER: Ma M

PROVIDER: S-EPMC8215574 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.IntroductionOsteoporosis 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.MethodsTo 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.ResultsOur 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.ConclusionsWe 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.