| Title: | Multisite Chronic Pain Reveals Neuro-Immune-Metabolic Dysregulation across Rheumatoid Arthritis and Depression |
| Journal: | Research |
| Published: | 1 Jan 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42317795/ |
| DOI: | https://doi.org/10.34133/research.1298 |
Publication 20662
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Abstract
Multisite chronic pain (MCP) frequently co-occurs with immune and depressive disorders, yet whether it reflects coordinated cross-domain multi-omic dysregulation remains unknown. Using UK Biobank data (19,484 baseline participants; 32,870 to 399,476 for 15.9-year follow-up), we identified MCP-related multi-omic signatures spanning 59 biochemical measures, 168 metabolites, and 2,920 proteins. Notably, these signatures showed graded dysregulation [controls < depression < rheumatoid arthritis (RA) < comorbidity] with increasing disease burden, were associated with increased risk of incident RA and depression, and partially mediated their bidirectional association. We further identified HNMT as a depression risk factor, FGF21 as an RA risk factor, MME as a depression protective factor, and platelet count/FGF21/HNMT as shared factors using Mendelian randomization. Beyond disease outcomes, the signatures were associated with brain structural impairment and health-related behaviors (smoking/fish intake/physical activity), and aligned with polygenic liability for immune-metabolic-psychiatric traits. Together, these findings demonstrate that MCP reflects coordinated neuro-immune-metabolic dysregulation underlying RA-depression comorbidity and functions as a systems-level phenotype linking immune processes and depression.</p>
15 Authors
- Qian Wang
- Ye Ella Tian
- Andrew Zalesky
- Peng Wang
- Zening Fu
- Guozheng Feng
- Dongmei Zhi
- Ming Xu
- Chunyang Wang
- Xiaoli Wang
- Xizhen Wang
- Peiwu Qin
- Vince D. Calhoun
- Rongtao Jiang
- Jing Sui
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