Multi-omic insight into the molecular networks of mitochondrial dysfunction in the pathogenesis of inflammatory bowel diseaseResearch in context
Summary: Background: Mitochondrial dysfunction has been linked to the development of inflammatory bowel disease (IBD), but the genetic pathophysiology was not fully elucidated. We employed Mendelian randomization and colocalization analyses to investigate the associations between mitochondrial-rela...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396423005005 |
| _version_ | 1797388796580331520 |
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| author | Jie Chen Xixian Ruan Yuhao Sun Shiyuan Lu Shixian Hu Shuai Yuan Xue Li |
| author_facet | Jie Chen Xixian Ruan Yuhao Sun Shiyuan Lu Shixian Hu Shuai Yuan Xue Li |
| author_sort | Jie Chen |
| collection | DOAJ |
| description | Summary: Background: Mitochondrial dysfunction has been linked to the development of inflammatory bowel disease (IBD), but the genetic pathophysiology was not fully elucidated. We employed Mendelian randomization and colocalization analyses to investigate the associations between mitochondrial-related genes and IBD via integrating multi-omics. Methods: Summary-level data of mitochondrial gene methylation, expression and protein abundance levels were obtained from corresponding methylation, expression and protein quantitative trait loci studies, respectively. We obtained genetic associations with IBD and its two subtypes from the Inflammatory Bowel Disease Genetics Consortium (discovery), the UK Biobank (replication), and the FinnGen study (replication). We performed summary-data-based Mendelian randomization analysis to assess the associations of mitochondrial gene-related molecular features with IBD. Colocalization analysis was further conducted to assess whether the identified signal pairs shared a causal genetic variant. Findings: After integrating the multi-omics data between mQTL-eQTL and eQTL-pQTL, we identified two mitochondrial genes, i.e., PARK7 and ACADM, with tier 1 evidence for their associations with IBD and ulcerative colitis (UC). PDK1 and FISI genes were associated with UC risk with tier 2 and tier 3 evidence, respectively. The methylation of cg05467918 in ACADM was associated with lower expression of ACADM, which fits with the positive effect of cg05467918 methylation on UC risk. Consistently, the inverse associations between gene methylation and gene expression were also observed in PARK7 (cg10385390) and PDK1 (cg17679246), which were corroborated with the protective role in UC. At circulating protein level, genetically predicted higher levels of PARK7 (OR 0.36, 95% CI 0.25–0.52) and HINT1 (OR 0.47, 95% CI 0.30–0.74) were inversely associated with IBD risk; genetically predicted higher level of HINT1 was associated with a decreased risk of Crohn's disease (CD) (OR 0.26, 95% CI 0.14–0.49) and a higher level of ACADM (OR 0.67, 95% CI 0.55–0.83), PDK1 (OR 0.63, 95% CI 0.49–0.81), FIS1 (OR 0.63, 95% CI 0.47–0.83) was associated with a decreased risk of UC. Interpretation: We found that the mitochondrial PARK7 gene was putatively associated with IBD risk, and mitochondrial FIS1, PDK1, and ACADM genes were associated with UC risk with evidence from multi-omics levels. This study identified mitochondrial genes in relation to IBD, which may enhance the understanding of the pathogenic mechanisms of IBD development. Funding: XL is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001) and Healthy Zhejiang One Million People Cohort (K-20230085). |
| first_indexed | 2024-03-08T22:46:02Z |
| format | Article |
| id | doaj.art-23ee806118374e2bba479809b8cffda9 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-03-08T22:46:02Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-23ee806118374e2bba479809b8cffda92023-12-17T06:38:35ZengElsevierEBioMedicine2352-39642024-01-0199104934Multi-omic insight into the molecular networks of mitochondrial dysfunction in the pathogenesis of inflammatory bowel diseaseResearch in contextJie Chen0Xixian Ruan1Yuhao Sun2Shiyuan Lu3Shixian Hu4Shuai Yuan5Xue Li6Department of Big Data in Health Science, School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaDepartment of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China; Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China; Corresponding author. Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Corresponding author.Department of Big Data in Health Science, School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Corresponding author.Summary: Background: Mitochondrial dysfunction has been linked to the development of inflammatory bowel disease (IBD), but the genetic pathophysiology was not fully elucidated. We employed Mendelian randomization and colocalization analyses to investigate the associations between mitochondrial-related genes and IBD via integrating multi-omics. Methods: Summary-level data of mitochondrial gene methylation, expression and protein abundance levels were obtained from corresponding methylation, expression and protein quantitative trait loci studies, respectively. We obtained genetic associations with IBD and its two subtypes from the Inflammatory Bowel Disease Genetics Consortium (discovery), the UK Biobank (replication), and the FinnGen study (replication). We performed summary-data-based Mendelian randomization analysis to assess the associations of mitochondrial gene-related molecular features with IBD. Colocalization analysis was further conducted to assess whether the identified signal pairs shared a causal genetic variant. Findings: After integrating the multi-omics data between mQTL-eQTL and eQTL-pQTL, we identified two mitochondrial genes, i.e., PARK7 and ACADM, with tier 1 evidence for their associations with IBD and ulcerative colitis (UC). PDK1 and FISI genes were associated with UC risk with tier 2 and tier 3 evidence, respectively. The methylation of cg05467918 in ACADM was associated with lower expression of ACADM, which fits with the positive effect of cg05467918 methylation on UC risk. Consistently, the inverse associations between gene methylation and gene expression were also observed in PARK7 (cg10385390) and PDK1 (cg17679246), which were corroborated with the protective role in UC. At circulating protein level, genetically predicted higher levels of PARK7 (OR 0.36, 95% CI 0.25–0.52) and HINT1 (OR 0.47, 95% CI 0.30–0.74) were inversely associated with IBD risk; genetically predicted higher level of HINT1 was associated with a decreased risk of Crohn's disease (CD) (OR 0.26, 95% CI 0.14–0.49) and a higher level of ACADM (OR 0.67, 95% CI 0.55–0.83), PDK1 (OR 0.63, 95% CI 0.49–0.81), FIS1 (OR 0.63, 95% CI 0.47–0.83) was associated with a decreased risk of UC. Interpretation: We found that the mitochondrial PARK7 gene was putatively associated with IBD risk, and mitochondrial FIS1, PDK1, and ACADM genes were associated with UC risk with evidence from multi-omics levels. This study identified mitochondrial genes in relation to IBD, which may enhance the understanding of the pathogenic mechanisms of IBD development. Funding: XL is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001) and Healthy Zhejiang One Million People Cohort (K-20230085).http://www.sciencedirect.com/science/article/pii/S2352396423005005Inflammatory bowel diseaseMendelian randomizationMitochondrionMethylationGene expressionProtein |
| spellingShingle | Jie Chen Xixian Ruan Yuhao Sun Shiyuan Lu Shixian Hu Shuai Yuan Xue Li Multi-omic insight into the molecular networks of mitochondrial dysfunction in the pathogenesis of inflammatory bowel diseaseResearch in context EBioMedicine Inflammatory bowel disease Mendelian randomization Mitochondrion Methylation Gene expression Protein |
| title | Multi-omic insight into the molecular networks of mitochondrial dysfunction in the pathogenesis of inflammatory bowel diseaseResearch in context |
| title_full | Multi-omic insight into the molecular networks of mitochondrial dysfunction in the pathogenesis of inflammatory bowel diseaseResearch in context |
| title_fullStr | Multi-omic insight into the molecular networks of mitochondrial dysfunction in the pathogenesis of inflammatory bowel diseaseResearch in context |
| title_full_unstemmed | Multi-omic insight into the molecular networks of mitochondrial dysfunction in the pathogenesis of inflammatory bowel diseaseResearch in context |
| title_short | Multi-omic insight into the molecular networks of mitochondrial dysfunction in the pathogenesis of inflammatory bowel diseaseResearch in context |
| title_sort | multi omic insight into the molecular networks of mitochondrial dysfunction in the pathogenesis of inflammatory bowel diseaseresearch in context |
| topic | Inflammatory bowel disease Mendelian randomization Mitochondrion Methylation Gene expression Protein |
| url | http://www.sciencedirect.com/science/article/pii/S2352396423005005 |
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