Causal role of immune cells in schizophrenia: Mendelian randomization (MR) study

Complex immune-brain interactions that affect neural development, survival and function might have causal and therapeutic implications for psychiatric illnesses. However, previous studies examining the association between immune inflammation and schizophrenia (SCZ) have yielded inconsistent findings.

Comprehensive two-sample Mendelian randomization (MR) analysis was performed to determine the causal association between immune cell signatures and SCZ in this study. Based on publicly available genetic data, we explored causal associations between 731 immune cell signatures and SCZ risk. A total of four types of immune signatures (median fluorescence intensities (MFI), relative cell (RC), absolute cell (AC), and morphological parameters (MP)) were included. Comprehensive sensitivity analyses were used to verify the robustness, heterogeneity, and horizontal pleiotropy of the results.

After FDR correction, SCZ had no statistically significant effect on immunophenotypes. It was worth mentioning some phenotypes with unadjusted low P-values, including FSC-A on NKT (β = 0.119, 95% CI = 0.044 ~ 0.194, P = 0.002), DN (CD4-CD8-) NKT %T cell (β = 0.131, 95% CI = 0.054 ~ 0.208, P = 9.03 × 10^- 4), and SSC-A on lymphocytes (β = 0.136, 95% CI = 0.059 ~ 0.213, P = 5.43 × 10^- 4). The causal effect of SCZ IgD on transitional was estimated to 0.127 (95% CI = 0.051 ~ 0.203, P = 1.09 × 10^- 3). SCZ also had a causal effect on IgD+ %B cell (β = 0.130, 95% CI = 0.054 ~ 0.207, P = 8.69 × 10^- 4), and DP (CD4⁺CD8⁺) %T cell (β = 0.131, 95% CI = 0.054 ~ 0.207, P = 8.05 × 10^- 4). Furthermore, four immunophenotypes were identified to be significantly associated with SCZ risk: naive CD4⁺ %T cell (OR = 0.986, 95% CI = 0.979 ~ 0.992, P = 1.37 × 10^- 5), HLA DR on CD14^- CD16^- (OR = 0.738 (95% CI = 0.642 ~ 0.849, P = 2.00 × 10^- 5), CD33^dim HLA DR⁺ CD11b^- AC (OR = 0.631, 95% CI = 0.529 ~ 0.753, P = 3.40 × 10^- 7) and activated & resting Treg % CD4 Treg (OR = 0.937, 95% CI = 0.906 ~ 0.970, P = 1.96 × 10^- 4).

Our study has demonstrated the close connection between immune cells and SCZ by genetic means, thus providing guidance for future clinical research.