This is the first bidirectional two-sample MR research that, to the best of our knowledge, examines the causal effects of six WBC characteristics in schizophrenia susceptibility. This MR study indicated that schizophrenia was positively associated with levels of WBC, lymphocyte, neutrophil, basophil, eosinophil, and monocyte. No evidence that six WBC count traits associated with schizophrenia was observed.
Leukocytes are an essential component of the body's immunological defense mechanism. In total, there are five types of leukocytes in the blood, namely neutrophils, eosinophils, basophils, lymphocytes and monocytes, each of which has its own physiological function. A recent meta-analysis showed that peripheral blood WBC count, neutrophil count, and monocyte count were significantly elevated in both patients with first-episode of psychosis (FEP) and chronic psychosis[28], which is consistent with the results of this study. However, possibly limited by heterogeneity between studies and small sample size, no correlation was found between several other categorical counts and schizophrenia in this meta-analysis. A newly published findings showed consistent results of elevated WBC and neutrophil counts in drug-naive FEP patients[29]. Several studies have pointed out that impaired inflammatory regulation represented by elevated WBC may be a manifestation of more severe neuropathological changes and a higher risk of metabolic syndrome in patients with schizophrenia[29–31]. And it is worth noting that schizophrenia patients with increased WBC and neutrophil counts may show a tendency for increased self-aggression [32]. Neutrophils, a complex of transcriptionally active cells, have multiple essential roles such as secreting cytokines, regulating the activity of neighboring cells, and regulating macrophages for long-term immune response[33]. As for the schizophrenia studies, in FEP patients, elevated neutrophil counts may serve as an important monitoring indicator and indirect evidence of reduced gray matter tissue, increased cerebrospinal fluid volume, higher PANSS scores, and more severe clinical presentation in patients[34]. The results of studies on lymphocyte counts in patients with schizophrenia are not yet consistent. Some studies suggested that patients with schizophrenia exhibit a blood cell pattern of increased neutrophils, decreased lymphocytes, and increased neutrophil to lymphocyte ratio[35, 36]. However, there is evidence indicating that pro-inflammatory-prone monocytes were significantly overrepresented and the T-lymphocyte network was significantly activated in patients with recurrent-onset schizophrenia[37]. In addition, a study of brain tissue from patients with schizophrenia and mood disorder found that high-density lymphocyte infiltration may predict the onset of neuroinflammation associated with blood-brain barrier damage[38]. The correlation between eosinophil and basophil counts and schizophrenia was less well studied. No differences in eosinophil counts between FEP patients and healthy controls have been observed[28]. However, some studies have indicated that eosinophil levels were are reduced in patients with FEP and tended to rebound with the course of treatment [39].
Current research has demonstrated that psychiatric disorders are closely linked to inflammatory responses, and the inflammatory immune mechanisms of schizophrenia have received extensive attention. On the one hand, patients with schizophrenia exhibit many characteristics of low-grade inflammation, for example, higher plasma levels of inflammatory cytokines, chemokines[29, 40, 41],and inducers [42]. On the other hand, studies have also suggested that the higher levels of inflammatory mediators are associated with the pathogenesis and disease progression of psychiatric disorders[40, 43]. Cytokines may enter the brain tissue associated with neurological disorders to drive neuroinflammation and activate the neuroendocrine axis, thereby triggering depressive behavior and cognitive impairment[44–46]. And numerous studies have also identified the association between immunomodulatory genes and the increased risk of several psychiatric disorders, such as schizophrenia and major depressive disorder [4, 47]. The results of the present study point to a significant unidirectional causal relationship between schizophrenia and WBC count traits, which may provide new evidence to support early inflammatory mechanisms in schizophrenic patients. Besides, this study for the first time suggests that schizophrenia may be potentially causally related to elevated levels of eosinophils and basophils, and further studies are needed to verify the causal relationship found in this study.
The main advantage of the present study is that we used a bidirectional IVs analysis to avoid reverse causality and confounding factors as much as possible. To address the inability of cross-sectional studies to determine causality, a potential causal association of neutrophils, lymphocytes on susceptibility to three psychiatric disorders (seminal schizophrenia, major depression, bipolar disorder) was explored in a bidirectional MR analysis published in 2021 using summary data published in a 2016 GWAS study (n = 173,480) [48], however the results were not significant, and vice versa[49]. In contrast, the results of the present study comprehensively showed a unidirectional positive correlation between schizophrenia and the levels of all six WBC count traits. This may be due to the fact that the sample size of GWAS data used in this study was 2.3 times larger than the data used in the previous MR study, and therefore this study had a higher power for causal association testing and more accurate estimated effect values. Also, this study used different methods to estimate the causal effects, and the mutually corroborating results made the causal effects more convincing. However, several limitations cannot be ignored in this study. First, although the funnel plots all showed a symmetrical distribution of IVs and the results of the leave-one-out analysis demonstrated the robustness of the results, Cochran 's Q values still showed the presence of heterogeneity. Second, although this study showed no horizontal pleiotropy by MR-Egger intercept test, some potentially pleiotropic IVs could not be completely excluded. Finally, the practical effects of IVs on outcome variables cannot yet be fully explained. Therefore, we highlight that the results of this study should be interpreted cautiously and more studies are needed in the future to elucidate and validate the leukocyte count changes in schizophrenia and their inflammatory mechanisms.