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<p>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 (r<sub>g</sub>: 0.11–0.49) and identified 128 pleiotropic genes, including <i>ZKSCAN4</i>, <i>BTN3A2</i>, and <i>HSPA1L</i>. 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>

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

  • 期刊论文

  • 发表日期：

    2026年2月4日

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  • 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

摘要

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.