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

Chengdong Wang; Dongdong Zhu; Dongjun Zhang; Xiaowei Zuo; Lei Yao; Teng Liu; Xiaodan Ge; Chenlu He; Yuan Zhou; Ziyuan Shen

doi:10.1186/s12888-023-05081-4

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

BMC Psychiatry. 2023 Aug 15;23(1):590. doi: 10.1186/s12888-023-05081-4.

Authors

Chengdong Wang¹, Dongdong Zhu¹, Dongjun Zhang^{2

3}, Xiaowei Zuo¹, Lei Yao¹, Teng Liu¹, Xiaodan Ge¹, Chenlu He⁴, Yuan Zhou⁵, Ziyuan Shen⁶

Affiliations

¹ Department of Psychiatry, The Affiliated Xuzhou Oriental Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
² School of Psychology, Xinxiang Medical University, Xinxiang, Henan, 453003, China.
³ Department of Psychiatry, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453005, China.
⁴ Department of Epidemiology and Biostatistics, School of Public Health, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
⁵ Medical Technology School of Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
⁶ Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, 230032, China. sshenzy@126.com.

Abstract

Background: 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.

Methods: 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.

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}).

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

Keywords: Brain; Causal inference; Immunity; MR analysis; Schizophrenia; Sensitivity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Brain
Genome-Wide Association Study
Humans
Inflammation
Mendelian Randomization Analysis
Phenotype
Schizophrenia* / genetics