Single-cell transcriptome-wide Mendelian randomization and colocalization reveals immune-mediated regulatory mechanisms and drug targets for COVID-19

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

doi:10.1016/j.ebiom.2025.105596

Single-cell transcriptome-wide Mendelian randomization and colocalization reveals immune-mediated regulatory mechanisms and drug targets for COVID-19

EBioMedicine. 2025 Mar:113:105596. doi: 10.1016/j.ebiom.2025.105596. Epub 2025 Feb 10.

Authors

Hui Ying¹, Xueyan Wu¹, Xiaojing Jia¹, Qianqian Yang¹, Haoyu Liu¹, Huiling Zhao², Zhihe Chen¹, Min Xu¹, Tiange Wang¹, Mian Li¹, Zhiyun Zhao¹, Ruizhi Zheng¹, Shuangyuan Wang¹, Hong Lin¹, Yu Xu¹, Jieli Lu¹, Weiqing Wang¹, Guang Ning¹, Jie Zheng³, Yufang Bi⁴

Affiliations

¹ 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.
² MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.
³ 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; MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK. Electronic address: zj12477@rjh.com.cn.
⁴ 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. Electronic address: byf10784@rjh.com.cn.

Abstract

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).

Keywords: Causal mechanisms; Drug target prioritization; Immune cell eQTL; Mendelian randomization; SARS-CoV-2.

MeSH terms

Antiviral Agents / pharmacology
Antiviral Agents / therapeutic use
COVID-19 Drug Treatment*
COVID-19* / genetics
COVID-19* / immunology
COVID-19* / virology
Genome-Wide Association Study
Host-Pathogen Interactions / genetics
Host-Pathogen Interactions / immunology
Humans
Mendelian Randomization Analysis
Polymorphism, Single Nucleotide
Quantitative Trait Loci
SARS-CoV-2
Single-Cell Analysis
Transcriptome*

Substances

Antiviral Agents