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Integrating Transcriptome-Wide Association Study and mRNA Expression Profiling Identifies Novel Genes Associated With Osteonecrosis of the Femoral Head
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-comput...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215574/ https://www.ncbi.nlm.nih.gov/pubmed/34163523 http://dx.doi.org/10.3389/fgene.2021.663080 |
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author | Ma, Mei Li, Peilin Liu, Li Cheng, Shiqiang Cheng, Bolun Liang, Chu Jun Tan, Sijia Li, Wenyu Wen, Yan Guo, Xiong Wu, Cuiyan |
author_facet | Ma, Mei Li, Peilin Liu, Li Cheng, Shiqiang Cheng, Bolun Liang, Chu Jun Tan, Sijia Li, Wenyu Wen, Yan Guo, Xiong Wu, Cuiyan |
author_sort | Ma, Mei |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8215574 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82155742021-06-22 Integrating Transcriptome-Wide Association Study and mRNA Expression Profiling Identifies Novel Genes Associated With Osteonecrosis of the Femoral Head Ma, Mei Li, Peilin Liu, Li Cheng, Shiqiang Cheng, Bolun Liang, Chu Jun Tan, Sijia Li, Wenyu Wen, Yan Guo, Xiong Wu, Cuiyan Front Genet Genetics 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. Frontiers Media S.A. 2021-06-07 /pmc/articles/PMC8215574/ /pubmed/34163523 http://dx.doi.org/10.3389/fgene.2021.663080 Text en Copyright © 2021 Ma, Li, Liu, Cheng, Cheng, Liang, Tan, Li, Wen, Guo and Wu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Genetics Ma, Mei Li, Peilin Liu, Li Cheng, Shiqiang Cheng, Bolun Liang, Chu Jun Tan, Sijia Li, Wenyu Wen, Yan Guo, Xiong Wu, Cuiyan Integrating Transcriptome-Wide Association Study and mRNA Expression Profiling Identifies Novel Genes Associated With Osteonecrosis of the Femoral Head |
title | Integrating Transcriptome-Wide Association Study and mRNA Expression Profiling Identifies Novel Genes Associated With Osteonecrosis of the Femoral Head |
title_full | Integrating Transcriptome-Wide Association Study and mRNA Expression Profiling Identifies Novel Genes Associated With Osteonecrosis of the Femoral Head |
title_fullStr | Integrating Transcriptome-Wide Association Study and mRNA Expression Profiling Identifies Novel Genes Associated With Osteonecrosis of the Femoral Head |
title_full_unstemmed | Integrating Transcriptome-Wide Association Study and mRNA Expression Profiling Identifies Novel Genes Associated With Osteonecrosis of the Femoral Head |
title_short | Integrating Transcriptome-Wide Association Study and mRNA Expression Profiling Identifies Novel Genes Associated With Osteonecrosis of the Femoral Head |
title_sort | integrating transcriptome-wide association study and mrna expression profiling identifies novel genes associated with osteonecrosis of the femoral head |
topic | Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215574/ https://www.ncbi.nlm.nih.gov/pubmed/34163523 http://dx.doi.org/10.3389/fgene.2021.663080 |
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