| Title: | Bidirectional association between immune-mediated diseases and major depressive disorder: evidence from cohort, genome-wide pleiotropic, and experimental studies |
| Journal: | Molecular Psychiatry |
| Published: | 4 Feb 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41639228/ |
| DOI: | https://doi.org/10.1038/s41380-026-03459-w |
Publication 18370
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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.</p>
19 Authors
- Xiaohua Chen
- Huan Liu
- Yurong Liu
- Cong Zhang
- Yimeng Ren
- Pengcheng Liu
- Shanshan Zhang
- Congjiao Li
- Qian Shen
- Siyue Wang
- Chenhui Zhang
- Qing Wang
- Xiangli Chen
- Ying Qu
- Mengjie Huang
- Jie Tang
- Xin Liu
- Wenzhen Gao
- Rong Zhong
1 Application
| Application ID | Title |
|---|---|
| 84980 | The Mendelian randomization of Metabolomics and Cancer |
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