{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:00:23Z","timestamp":1753891223666,"version":"3.41.2"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,7]],"date-time":"2021-06-07T00:00:00Z","timestamp":1623024000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>This study aims to identify novel candidate genes associated with osteonecrosis of the femoral head (ONFH).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats: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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>TWAS totally identified 564 genes that were with <jats:italic>P<\/jats:italic><jats:sub>TWAS<\/jats:sub> value &amp;lt;0.05 for MS and blood, such as <jats:italic>CBX1<\/jats:italic> (<jats:italic>P<\/jats:italic><jats:sub>TWAS<\/jats:sub> = 0.0001 for MS), <jats:italic>SRPK2<\/jats:italic> (<jats:italic>P<\/jats:italic><jats:sub>TWAS<\/jats:sub> = 0.0002 for blood), and <jats:italic>MYO5A<\/jats:italic> (<jats:italic>P<\/jats:italic><jats:sub>TWAS<\/jats: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 <jats:italic>STEAP4<\/jats:italic> [<jats:italic>P<\/jats:italic><jats:sub>TWAS<\/jats:sub> = 0.0270, FC (fold change)<jats:sub>mRNA<\/jats:sub> = 7.03], <jats:italic>RABEP1<\/jats:italic> (<jats:italic>P<\/jats:italic><jats:sub>TWAS<\/jats:sub> = 0.010, FC<jats:sub>mRNA<\/jats:sub> = 2.22), and <jats:italic>MORC3<\/jats:italic> (<jats:italic>P<\/jats:italic><jats:sub>TWAS<\/jats:sub> = 0.0053, FC<jats:sub>mRNA<\/jats: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 (<jats:italic>P<\/jats:italic><jats:sub>TWAS<\/jats:sub> = 0.0006, <jats:italic>P<\/jats:italic><jats:sub>mRNA<\/jats:sub> = 0.0227), extracellular space (<jats:italic>P<\/jats:italic><jats:sub>TWAS<\/jats:sub> = 0.0342, <jats:italic>P<\/jats:italic><jats:sub>mRNA<\/jats:sub> = 0.0012), protein binding (<jats:italic>P<\/jats:italic><jats:sub>TWAS<\/jats:sub> = 0.0112, <jats:italic>P<\/jats:italic><jats:sub>mRNA<\/jats:sub> = 0.0106), and ATP binding (<jats:italic>P<\/jats:italic><jats:sub>TWAS<\/jats:sub> = 0.0464, <jats:italic>P<\/jats:italic><jats:sub>mRNA<\/jats:sub> = 0.0033).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats: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.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fgene.2021.663080","type":"journal-article","created":{"date-parts":[[2021,6,7]],"date-time":"2021-06-07T06:53:00Z","timestamp":1623048780000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Integrating Transcriptome-Wide Association Study and mRNA Expression Profiling Identifies Novel Genes Associated With Osteonecrosis of the Femoral Head"],"prefix":"10.3389","volume":"12","author":[{"given":"Mei","family":"Ma","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peilin","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiqiang","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bolun","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chu Jun","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sijia","family":"Tan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Wen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiong","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cuiyan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1007\/s10142-009-0147-6","article-title":"Genes influencing spinal bone mineral density in inbred F344, LEW, COP, and DA rats.","volume":"10","author":"Alam","year":"2010","journal-title":"Funct. 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