The causal relationship between immune cell traits and schizophrenia: a Mendelian randomization analysis

Introduction: The complex and unresolved pathogenesis of schizophrenia has posed significant challenges to its diagnosis and treatment. While recent research has established a clear association between immune function and schizophrenia, the causal relationship between the two remains elusive. Methods: We employed a bidirectional two-sample Mendelian randomization approach to investigate the causal relationship between schizophrenia and 731 immune cell traits by utilizing public GWAS data. We further validated the causal relationship between schizophrenia and six types of white cell measures. Results: We found the overall causal effects of schizophrenia on immune cell traits were significantly higher than the reverse ones (0.011 +/- 0.049 vs 0.001 +/- 0.016, p < 0.001), implying that disease may lead to an increase in immune cells by itself. We also identified four immune cell traits that may increase the risk of schizophrenia: CD11c+ monocyte %monocyte (odds ratio (OR): 1.06, 95% confidence interval (CI): 1.03 similar to 1.09, FDR = 0.027), CD11c+ CD62L- monocyte %monocyte (OR:1.06, 95% CI: 1.03 similar to 1.09, FDR = 0.027), CD25 on IgD+ CD38-naive B cell (OR:1.03, 95% CI:1.01 similar to 1.06, FDR = 0.042), and CD86 on monocyte (OR = 1.04, 95% CI:1.01 similar to 1.06, FDR = 0.042). However, we did not detect any significant causal effects of schizophrenia on immune cell traits. Using the white blood cell traits data, we identified that schizophrenia increases the lymphocyte counts (OR:1.03, 95%CI: 1.01-1.04, FDR = 0.007), total white blood cell counts (OR:1.02, 95%CI: 1.01-1.04, FDR = 0.021) and monocyte counts (OR:1.02, 95%CI: 1.00-1.03, FDR = 0.034). The lymphocyte counts were nominally associated with the risk of schizophrenia (OR:1.08,95%CI:1.01-1.16, P=0.019). Discussion: Our study found that the causal relationship between schizophrenia and the immune system is complex, enhancing our understanding of the role of immune regulation in the development of this disorder. These findings offer new insights for exploring diagnostic and therapeutic options for schizophrenia.