2026 ECNP Congress

PS04-4085

Regulatory T-cell transcriptomic signatures shared across psychosis and cardiometabolic outcomes

Fabiana Corsi-Zuelli — R. Upthegrove, D. Rosoff · University of Oxford, Department of Psychiatry, Oxford, United Kingdom

2026 ECNP Congress

Background

Regulatory T cells (Tregs) are central orchestrators of immune and brain homeostasis [1,2], and immune dysregulation is increasingly implicated across psychosis and cardiometabolic disease [3]. However, the shared regulatory T-cell transcriptomic architecture underlying psychiatric and cardiometabolic outcomes remains unknown. Methods.We performed two-sample Mendelian randomisation (MR) using publicly available summary statistics for cis-expression quantitative trait loci (cis-eQTLs) from human regulatory T cells (Tregs) across three activation states: resting (0h), early-activated (16h), and late-activated (40h). Instrumental variables were selected using an F-statistic threshold >10. MR analyses were conducted using inverse-variance weighted (IVW) and linkage disequilibrium-aware probabilistic constrained generalized method of moments (LD-PCGMM) approaches, with Benjamini–Hochberg false discovery rate (FDR) correction applied within each method. A total of 3,818 Treg-expressed genes were tested against schizophrenia (SCZ) GWAS summary statistics. Genes reaching FDR <0.05 for SCZ (“anchor genes”) were subsequently evaluated across four cardiometabolic outcomes: coronary artery disease, type 2 diabetes, triglyceride-to-HDL ratio, and non-ischaemic heart failure. Results After FDR correction, 88 unique Treg-expressed genes were associated with SCZ risk, corresponding to 98 gene × activation-state × method associations. Associations increased across Treg activation states, with 21 genes detected at resting state (0h), 31 at early activation (16h), and 40 at late activation (40h), suggesting enrichment of SCZ-relevant genetic signal in activated Treg states. Most associated genes mapped outside the MHC region (56/88, 64%). Direction-of-effect analyses indicated 39 genes associated with potential increased SCZ risk, 48 with potential reduced risk, and one gene showing mixed direction across analyses. Leading non-MHC associations, ranked by FDR, included genes expressed during late activation (40h), e.g., MRS2 (OR 0.80, 95% CI 0.74–0.86; FDR = 1.32 × 10⁻⁶), MAN2A2 (OR 0.60, 95% CI 0.50–0.72; FDR = 5.62 × 10⁻⁶), and LRRC16A (OR 0.69, 95% CI 0.60–0.79; FDR = 2.79 × 10⁻⁵). Within the MHC, leading associations included genes at resting state (0h) e.g., NFKBIL1 (OR 0.90, 95% CI 0.88–0.92; FDR = 2.12 × 10⁻¹⁶), and HLA-DRB5 (OR 1.50, 95% CI 1.34–1.68; FDR = 6.56 × 10⁻¹⁰). Cross-trait analysis showed that 38 of the 88 SCZ-associated Treg genes also overlapped with at least one cardiometabolic outcome: 4 with coronary artery disease, 21 with type 2 diabetes, and 25 with triglyceride/HDL ratio. No FDR-significant overlap was observed with non-ischaemic heart failure. Overall, 50 genes appeared SCZ-specific within the outcomes tested.Conclusion Cis-eQTL MR identified an activation-dependent regulatory T-cell transcriptomic signature associated with SCZ risk, with leading non-MHC associations emerging primarily during late Treg activation. Functionally, implicated genes converged on mitochondrial metabolism, immune-cell signalling, cytoskeletal regulation, protein processing and MHC-mediated antigen presentation. The overlap between SCZ-associated Treg genes and cardiometabolic traits suggests potential shared immune-regulatory mechanisms across psychiatric and metabolic outcomes. Further analyses are underway to identify shared common causal variants.

References

  1. Corsi-Zuelli F, Deakin B. Impaired regulatory T-cell control of astroglial overdrive and microglial pruning in schizophrenia. Neurosci Biobehav Rev. 2021;125:637-653. doi:10.1016/j.neubiorev.2021.03.004
  2. Corsi-Zuelli F, Deakin B, de Lima MHF, Qureshi O, Barnes NM, Upthegrove R, Louzada-Junior P, Del-Ben CM. T regulatory cells as a potential therapeutic target in psychosis? Current challenges and future perspectives. Brain Behav Immun Health. 2021;17:100330. doi:10.1016/j.bbih.2021.100330
  3. Upthegrove R, Corsi-Zuelli F, Couch ACM, Barnes NM, Vernon AC. Current position and future direction of inflammation in neuropsychiatric disorders: a review. JAMA Psychiatry. 2025;82(10):1030-1046. doi:10.1001/jamapsychiatry.2025.1369