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

Abstract

ObjectiveThis study aims to identify novel candidate genes associated with osteonecrosis of the femoral head (ONFH).MethodsA 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.ResultsTWAS totally identified 564 genes that were with PTWAS value <0.05 for MS and blood, such as CBX1 (PTWAS = 0.0001 for MS), SRPK2 (PTWAS = 0.0002 for blood), and MYO5A (PTWAS = 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 [PTWAS = 0.0270, FC (fold change)mRNA = 7.03], RABEP1 (PTWAS = 0.010, FCmRNA = 2.22), and MORC3 (PTWAS = 0.0053, FCmRNA = 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 (PTWAS = 0.0006, PmRNA = 0.0227), extracellular space (PTWAS = 0.0342, PmRNA = 0.0012), protein binding (PTWAS = 0.0112, PmRNA = 0.0106), and ATP binding (PTWAS = 0.0464, PmRNA = 0.0033).ConclusionSeveral 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.