| Title: | B cell pathways implicate shared genetic architecture between schizophrenia and immune-mediated diseases |
| Journal: | Journal of Translational Medicine |
| Published: | 14 Jan 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41535972/ |
| DOI: | https://doi.org/10.1186/s12967-025-07667-w |
Publication 18527
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Abstract
BackgroundSchizophrenia and immune-mediated diseases are globally prevalent and highly heritable conditions that frequently co-occur, posing major public health burdens. However, their shared genetic architecture remains poorly understood.MethodsWe applied the bivariate causal mixture model (MiXeR) to investigate the polygenic overlap between schizophrenia and eight common immune-mediated diseases, using genome-wide association study summary statistics comprising 2,489 to 67,323 cases and 9,066 to 497,622 controls. Shared loci were identified through conditional/conjunctional false discovery rate (cond/conjFDR), local genetic correlation (LAVA), and colocalization analyses. Subsequently, gene mapping, functional annotation, expression-trait association, and drug-gene interaction analyses were performed to explore shared genes and enriched pathways, and genetic risk scores (GRS) from the UK Biobank were used to validate the findings.ResultsMiXeR estimated substantial polygenic overlap between schizophrenia and immune-mediated diseases, and conjFDR identified 133 shared loci, with eight prioritized through local genetic correlation and colocalization signals. These eight loci were mapped to 85 protein-coding genes enriched in pathways essential for B cell function. Among them, S-PrediXcan analyses identified 14 genes whose expression in brain tissues or blood was associated with both diseases. These genes also interact with immunomodulatory or antihypertensive drugs. Additionally, 11 of the 14 genes were linked to innate immunity and/or cognitive traits. Using UK Biobank data, we further confirmed that overall, shared gene, and B cell activation and receptor signaling pathway-specific genetic risk for schizophrenia is associated with immune-mediated disease susceptibility.ConclusionsThese findings underscore the shared genetic architecture of schizophrenia and immune-mediated diseases, advancing insights at the interface of psychiatric genetics and immunology.</p>
13 Authors
- Rui Yuan
- Yunqing Zhu
- Yuyanan Zhang
- Yaoyao Sun
- Zhe Lu
- Zhewei Kang
- Xiaoyang Feng
- Junyuan Sun
- Guorui Zhao
- Jing Guo
- Tong Yu
- Wenjian Bi
- Weihua Yue
1 Application
| Application ID | Title |
|---|---|
| 78795 | Regression methods for phenome-wide association analysis on large-scale biobank data |
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