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.
Highlights
Osteonecrosis (ON) is a common orthopedic disorder, the pathological features of which is the death of bone cells owing to the decrease of blood flow (Assouline-Dayan et al, 2002)
A trans-omics comparative analysis of transcriptome-wide association study (TWAS) and genome-wide mRNA expression profiling was conducted to identify the common genes and the gene ontology (GO) terms shared by both DNA-level TWAS and mRNA-level expression profile for ONFH
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, FCmRNA = 7.03], RABEP1 (PTWAS = 0.010, FCmRNA = 2.22), and MORC3 (PTWAS = 0.0053, FCmRNA = 2.92)
Summary
Osteonecrosis (ON) is a common orthopedic disorder, the pathological features of which is the death of bone cells owing to the decrease of blood flow (Assouline-Dayan et al, 2002). A number of genetic factors for ON have been conducted, linking specific genes or susceptibility loci to the pathogenesis of ON (Hadjigeorgiou et al, 2008; Karol et al, 2015; Sun et al, 2015; Zhou et al, 2015). A meta-analysis study reported that vascular endothelial growth factors, endothelial nitric oxide synthase, and ATP-binding cassette subfamily B member 1 transporter (ABCB1) polymorphisms were associated with the risk of ONFH (Zhou et al, 2015). The genetic polymorphisms in ABCB1 gene (C3435T), apolipo-protein B (ApoB) gene (C7623T), and cAMPresponse element binding protein-binding protein (CBP) gene (rs3751845) increased and were helpful for predicting the risk of steroid-induced ONFH (Kuribayashi et al, 2008).
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