Single-cell transcriptome-wide Mendelian randomization and colocalization reveals immune-mediated regulatory mechanisms and drug targets for COVID-19Research in context
Summary: Background: COVID-19 continues to show long-term impacts on our health. Limited effective immune-mediated antiviral drugs have been launched. Methods: We conducted a Mendelian randomization (MR) and colocalization analysis using 26,597 single-cell expression quantitative trait loci (sc-eQT...
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Elsevier
2025-03-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396425000404 |
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| author | Hui Ying Xueyan Wu Xiaojing Jia Qianqian Yang Haoyu Liu Huiling Zhao Zhihe Chen Min Xu Tiange Wang Mian Li Zhiyun Zhao Ruizhi Zheng Shuangyuan Wang Hong Lin Yu Xu Jieli Lu Weiqing Wang Guang Ning Jie Zheng Yufang Bi |
| author_facet | Hui Ying Xueyan Wu Xiaojing Jia Qianqian Yang Haoyu Liu Huiling Zhao Zhihe Chen Min Xu Tiange Wang Mian Li Zhiyun Zhao Ruizhi Zheng Shuangyuan Wang Hong Lin Yu Xu Jieli Lu Weiqing Wang Guang Ning Jie Zheng Yufang Bi |
| author_sort | Hui Ying |
| collection | DOAJ |
| description | Summary: Background: COVID-19 continues to show long-term impacts on our health. Limited effective immune-mediated antiviral drugs have been launched. Methods: We conducted a Mendelian randomization (MR) and colocalization analysis using 26,597 single-cell expression quantitative trait loci (sc-eQTL) to proxy effects of expressions of 16,597 genes in 14 peripheral blood immune cells and tested them against four COVID-19 outcomes from COVID-19 Genetic Housing Initiative GWAS meta-analysis Round 7. We also carried out additional validations including colocalization, linkage disequilibrium check and host–pathogen interactome predictions. We integrated MR findings with clinical trial evidence from several drug gene related databases to identify drugs with repurposing potential. Finally, we developed a tier system and identified immune-cell-based prioritized drug targets for COVID-19. Findings: We identified 132 putative causal genes in 14 immune cells (343 MR associations) for COVID-19, with 58 genes that were not reported previously. 145 (73%) gene-COVID-19 pairs showed effects on COVID-19 in only one immune cell type, which implied widespread immune-cell specific effects. For pathway analyses, we found the putative causal genes were enriched in natural killer (NK) recruiting cells but de-enriched in NK cells. Using a deep learning model, we found 107 (81%) of the putative causal genes (41 novel genes) were predicted to interact with SARS-COV-2 proteins. Integrating the above evidence with drug trial information, we developed a tier system and prioritized 37 drug targets for COVID-19. Interpretation: Our study showcased the central role of immune-mediated regulatory mechanisms for COVID-19 and prioritized drug targets that might inform interventions for viral infectious diseases. Funding: This work was supported by grants from the National Key Research and Development Program of China (2022YFC2505203). |
| format | Article |
| id | doaj-art-3a9a71b16a2d440f9691df3d9d9b2e6c |
| institution | Kabale University |
| issn | 2352-3964 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
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| series | EBioMedicine |
| spelling | doaj-art-3a9a71b16a2d440f9691df3d9d9b2e6c2025-02-11T04:35:00ZengElsevierEBioMedicine2352-39642025-03-01113105596Single-cell transcriptome-wide Mendelian randomization and colocalization reveals immune-mediated regulatory mechanisms and drug targets for COVID-19Research in contextHui Ying0Xueyan Wu1Xiaojing Jia2Qianqian Yang3Haoyu Liu4Huiling Zhao5Zhihe Chen6Min Xu7Tiange Wang8Mian Li9Zhiyun Zhao10Ruizhi Zheng11Shuangyuan Wang12Hong Lin13Yu Xu14Jieli Lu15Weiqing Wang16Guang Ning17Jie Zheng18Yufang Bi19Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaMRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UKDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK; Corresponding author. Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Corresponding author. Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.Summary: Background: COVID-19 continues to show long-term impacts on our health. Limited effective immune-mediated antiviral drugs have been launched. Methods: We conducted a Mendelian randomization (MR) and colocalization analysis using 26,597 single-cell expression quantitative trait loci (sc-eQTL) to proxy effects of expressions of 16,597 genes in 14 peripheral blood immune cells and tested them against four COVID-19 outcomes from COVID-19 Genetic Housing Initiative GWAS meta-analysis Round 7. We also carried out additional validations including colocalization, linkage disequilibrium check and host–pathogen interactome predictions. We integrated MR findings with clinical trial evidence from several drug gene related databases to identify drugs with repurposing potential. Finally, we developed a tier system and identified immune-cell-based prioritized drug targets for COVID-19. Findings: We identified 132 putative causal genes in 14 immune cells (343 MR associations) for COVID-19, with 58 genes that were not reported previously. 145 (73%) gene-COVID-19 pairs showed effects on COVID-19 in only one immune cell type, which implied widespread immune-cell specific effects. For pathway analyses, we found the putative causal genes were enriched in natural killer (NK) recruiting cells but de-enriched in NK cells. Using a deep learning model, we found 107 (81%) of the putative causal genes (41 novel genes) were predicted to interact with SARS-COV-2 proteins. Integrating the above evidence with drug trial information, we developed a tier system and prioritized 37 drug targets for COVID-19. Interpretation: Our study showcased the central role of immune-mediated regulatory mechanisms for COVID-19 and prioritized drug targets that might inform interventions for viral infectious diseases. Funding: This work was supported by grants from the National Key Research and Development Program of China (2022YFC2505203).http://www.sciencedirect.com/science/article/pii/S2352396425000404SARS-CoV-2Immune cell eQTLCausal mechanismsDrug target prioritizationMendelian randomization |
| spellingShingle | Hui Ying Xueyan Wu Xiaojing Jia Qianqian Yang Haoyu Liu Huiling Zhao Zhihe Chen Min Xu Tiange Wang Mian Li Zhiyun Zhao Ruizhi Zheng Shuangyuan Wang Hong Lin Yu Xu Jieli Lu Weiqing Wang Guang Ning Jie Zheng Yufang Bi Single-cell transcriptome-wide Mendelian randomization and colocalization reveals immune-mediated regulatory mechanisms and drug targets for COVID-19Research in context EBioMedicine SARS-CoV-2 Immune cell eQTL Causal mechanisms Drug target prioritization Mendelian randomization |
| title | Single-cell transcriptome-wide Mendelian randomization and colocalization reveals immune-mediated regulatory mechanisms and drug targets for COVID-19Research in context |
| title_full | Single-cell transcriptome-wide Mendelian randomization and colocalization reveals immune-mediated regulatory mechanisms and drug targets for COVID-19Research in context |
| title_fullStr | Single-cell transcriptome-wide Mendelian randomization and colocalization reveals immune-mediated regulatory mechanisms and drug targets for COVID-19Research in context |
| title_full_unstemmed | Single-cell transcriptome-wide Mendelian randomization and colocalization reveals immune-mediated regulatory mechanisms and drug targets for COVID-19Research in context |
| title_short | Single-cell transcriptome-wide Mendelian randomization and colocalization reveals immune-mediated regulatory mechanisms and drug targets for COVID-19Research in context |
| title_sort | single cell transcriptome wide mendelian randomization and colocalization reveals immune mediated regulatory mechanisms and drug targets for covid 19research in context |
| topic | SARS-CoV-2 Immune cell eQTL Causal mechanisms Drug target prioritization Mendelian randomization |
| url | http://www.sciencedirect.com/science/article/pii/S2352396425000404 |
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