Mendelian randomization analysis of causal and druggable circulating inflammatory proteins in schizophrenia

Background: Schizophrenia (SZ) is a severe mental disorder with complex origins. Observational studies suggested that inflammatory factors may play a role in the pathophysiology of SZ and we aim to investigate the potential genetic connection between them by examining the causal impact of circulating inflammatory proteins on SZ. Methods: We utilized Mendelian randomization (MR) analysis to assess the causal relationship between circulating inflammatory proteins and SZ and the GWAS summary datasets were sourced from public databases. The SZ dataset comprised 74,776 cases and 101,023 controls, while the summary results for 91 plasma proteins in 14,824 participants were obtained through the Olink Target platform. Moreover, to identify and evaluate potential drug targets, we searched the Drug-Gene Interaction Database (DGIdb). Results: The results of the MR study confirmed that nine inflammatory proteins had a causal effect on SZ. Among these proteins, IL1A (OR: 0.93), TNFB (OR: 0.94), TNFSF14 (OR: 0.96), and CD40 (OR: 0.95) exhibited protective effects against SZ. Conversely, CCL23 (OR: 1.04), CCL19 (OR: 1.04), 4EBP1 (OR: 1.06), TWEAK (OR: 1.08), and DNER (OR: 1.10) were associated with an increased risk of SZ. The MR-Egger and weighted median methods also supported the direction of these effects. According to the Gene-Drug analysis, LTA, IL1A, CD40, and 4EBP1 can serve as drug targets. Conclusions: Our study established causal relationships between circulating inflammatory proteins and SZ. It may be beneficial to personalize the treatment of SZ by incorporating inflammation management into the treatment regimen.