AUTHOR=Ma Mei , Li Peilin , Liu Li , Cheng Shiqiang , Cheng Bolun , Liang Chu Jun , Tan Sijia , Li Wenyu , Wen Yan , Guo Xiong , Wu Cuiyan 

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

JOURNAL=Frontiers in Genetics

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.663080

DOI=10.3389/fgene.2021.663080

ISSN=1664-8021

ABSTRACT=<sec><title>Objective</title><p>This study aims to identify novel candidate genes associated with osteonecrosis of the femoral head (ONFH).</p></sec><sec><title>Methods</title><p>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.</p></sec><sec><title>Results</title><p>TWAS totally identified 564 genes that were with <italic>P</italic><sub>TWAS</sub> value &lt;0.05 for MS and blood, such as <italic>CBX1</italic> (<italic>P</italic><sub>TWAS</sub> = 0.0001 for MS), <italic>SRPK2</italic> (<italic>P</italic><sub>TWAS</sub> = 0.0002 for blood), and <italic>MYO5A</italic> (<italic>P</italic><sub>TWAS</sub> = 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 <italic>STEAP4</italic> [<italic>P</italic><sub>TWAS</sub> = 0.0270, FC (fold change)<sub>mRNA</sub> = 7.03], <italic>RABEP1</italic> (<italic>P</italic><sub>TWAS</sub> = 0.010, FC<sub>mRNA</sub> = 2.22), and <italic>MORC3</italic> (<italic>P</italic><sub>TWAS</sub> = 0.0053, FC<sub>mRNA</sub> = 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 (<italic>P</italic><sub>TWAS</sub> = 0.0006, <italic>P</italic><sub>mRNA</sub> = 0.0227), extracellular space (<italic>P</italic><sub>TWAS</sub> = 0.0342, <italic>P</italic><sub>mRNA</sub> = 0.0012), protein binding (<italic>P</italic><sub>TWAS</sub> = 0.0112, <italic>P</italic><sub>mRNA</sub> = 0.0106), and ATP binding (<italic>P</italic><sub>TWAS</sub> = 0.0464, <italic>P</italic><sub>mRNA</sub> = 0.0033).</p></sec><sec><title>Conclusion</title><p>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.</p></sec>