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Bidirectional association between immune-mediated diseases and major depressive disorder: evidence from cohort, genome-wide pleiotropic, and experimental studies

Molecular Psychiatry (2026)Cite this article

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Abstract

Although immune-mediated diseases (IMDs) and major depressive disorder (MDD) commonly co-occur, the bidirectional relationship between them remains to be fully elucidated. Using data from the prospective UK Biobank cohort, we evaluated the bidirectional associations by time-varying Cox proportional hazards regression models and assessed shared genetic architecture using genome-wide association study summary statistics. Additionally, we employed collagen-induced arthritis (CIA) and chronic social defeat stress (CSDS) mouse models to investigate the relationship between rheumatoid arthritis (RA) and depression. Over 5,226,841 person-years of follow-up, 23,534 incident MDD cases were identified. The presence of any IMD was associated with higher MDD risk (hazard ratio [HR]: 1.95; 95% CI: 1.89–2.01). Conversely, 59,742 incident cases of IMD were documented. MDD was associated with increased IMD risk (HR: 1.47; 95% CI: 1.40–1.54). We observed significant global genetic correlations between IMDs and MDD (rg: 0.11–0.49) and identified 128 pleiotropic genes, including ZKSCAN4, BTN3A2, and HSPA1L. Clinically, RA patients exhibited systemic inflammation and decreased levels of brain-derived neurotrophic factor. In experimental models, CIA mice showed depressive-like behaviors and lesions in brain regions implicated in depression. Moreover, superimposing CSDS on CIA exacerbated depressive-like behavior and pain sensitivity, accelerated the onset and progression of arthritis, and heightened joint inflammation. Collectively, these population, genetic, and experimental findings support a bidirectional association and shared genetic susceptibility between IMDs and MDD, highlighting immune-neurobiological pathways, particularly those involving inflammation and neurotrophin dysregulation, as candidates for mechanistic dissection and therapeutic targets.

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Fig. 1: Association of IMDs with MDD risk.
Fig. 2: Association of IMD multimorbidity with MDD risk.
Fig. 3: Association of MDD with incident IMDs.
Fig. 4: Results of genetic correlation and genetic pleiotropic analyses.
Fig. 5: Depression-like behaviors in mice with collagen-induced arthritis.
Fig. 6: CSDS promotes the progression of CIA in mice.

Data availability

UK Biobank data are available by application (https://www.ukbiobank.ac.uk/enable-your-research/register).

Code availability

Codes for statistical analysis can be shared upon request.

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Acknowledgements

This work was supported by the Young Top-notch Talent Cultivation Program of Hubei Province. We are grateful to the participants and staff of the UK Biobank. This study was performed using data from the UK Biobank under Application 84980. The computation is completed in the HPC Platform of Huazhong University of Science and Technology.

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  1. These authors contributed equally: Xiaohua Chen, Huan Liu, Yurong Liu.

Authors and Affiliations

  1. Department of Laboratory Medicine, General Hospital of Central Theater Command, Wuhan, 430070, China

    Xiaohua Chen, Yurong Liu, Yimeng Ren, Congjiao Li, Xin Liu & Wenzhen Gao

  2. Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Huan Liu, Cong Zhang, Pengcheng Liu, Shanshan Zhang, Qian Shen, Siyue Wang, Chenhui Zhang, Qing Wang, Xiangli Chen, Ying Qu, Mengjie Huang, Jie Tang & Rong Zhong

  3. The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China

    Yurong Liu

  4. School of Laboratory Medicine, Hubei University of Chinese Medicine, 16 Huangjia Lake West Road, Wuhan, 430065, China

    Yimeng Ren

  5. Department of Laboratory Medicine, Hubei University of Medicine, Shiyan, 442000, China

    Congjiao Li

  6. Organ Transplantation Clinical Medical Research Center of Hubei Province, Wuhan, 430030, China

    Rong Zhong

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Contributions

RZ developed the main concept, designed the study, and contributed to drafting, writing, and critical revision of the manuscript. XC (Xiaohua Chen), HL, and YL performed data analysis and interpretation, and drafted the manuscript. YL, YR, CL, XL, and WG conducted the experiments. CZ (Cong Zhang), PL, SZ, QS, SW, and CZ (Chenhui Zhang) contributed to the editing and critical revision of important intellectual content. QW, XC (Xiangli Chen), YQ, MH, and JT contributed to data collection. All authors contributed to the review and revision of the manuscript.

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Correspondence to Rong Zhong.

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Chen, X., Liu, H., Liu, Y. et al. Bidirectional association between immune-mediated diseases and major depressive disorder: evidence from cohort, genome-wide pleiotropic, and experimental studies. Mol Psychiatry (2026). https://doi.org/10.1038/s41380-026-03459-w

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