Genome-wide expression in veterans with schizophrenia further validates the immune hypothesis for schizophrenia

Abstract

This study aimed to test whether a dysregulation of gene expression may be the underlying cause of previously reported elevated levels of inflammatory cytokines in veterans with schizophrenia. We performed a genome-wide expression analysis in peripheral blood mononuclear cells from veterans with schizophrenia and controls, and our results show that 167 genes and putative loci were differently expressed between groups. These genes were enriched primarily for pathways related to inflammatory mechanisms and formed networks related to cell death and survival, immune cell trafficking, among others, which is in line with previous reports and further validates the inflammatory hypothesis of schizophrenia.

Introduction

In addition to the most commonly studied mechanisms involving monoamines and acetylcholine in schizophrenia (which form the underlying basis of most of the currently available antipsychotic drugs), a growing body of evidence suggests a key role for inflammation in its pathophysiology (Khandaker and Dantzer, 2016). It is known that the interaction between the immune system and the brain can induce alterations in mood, cognition and behavior (Dantzer et al., 2008, Khandaker and Dantzer, 2016), and this immune-to-brain communication might play a key role in the pathophysiology and treatment of schizophrenia. Accordingly, patients with schizophrenia present a higher risk of developing auto-immune disorders (Benros et al., 2011) and show an imbalance between pro- and anti-inflammatory cytokines (Girgis et al., 2014). In addition, prenatal exposure to pathogenic microbes can increase the risk for the disorder (Brown and Derkits, 2010), suggesting a role for inflammatory cytokines in schizophrenia risk (Girgis et al., 2014).

In this context, we have previously shown that veterans with a diagnosis of schizophrenia exhibit an increased number of peripheral monocytes during episodes (Dimitrov, 2011), increased peripheral levels of GRO, MCP-1, MDC, and sCD40L, as well as decreased levels of IFN-γ, interleukin (IL)-2, IL-12p70, and IL-17, when compared to controls (Dimitrov et al., 2013). Moreover, more severe psychopathology in these patients, as assessed by the Positive and Negative Symptoms Scale (PANSS), was significantly correlated with molecules involved in the IL-17 pathway (Dimitrov et al., 2013) and with higher levels of high-sensitivity C-reactive protein (hsCRP) (Dimitrov et al., 2016). A follow-up sequential visit study confirmed the consistent increase in GRO, MCP-1, MDC, and sCD40L levels in patients across visits, as well as the decrease in IFN-γ levels (Dimitrov et al., 2015), while IL-17 and IL-4 were reduced only in specific visits (Dimitrov et al., 2015).

In another line of studies, genome-wide expression analyses, both in the periphery and the brain of patients with schizophrenia, have consistently shown alterations in immune system genes (Gardiner et al., 2013, Kumarasinghe et al., 2013, Narayan et al., 2008, Xu et al., 2012, Zheutlin et al., 2016), some of which are corrected by antipsychotic medications (Kumarasinghe et al., 2013). This dysregulation of gene expression may be the underlying cause of the elevated levels of inflammatory cytokines consistently observed in schizophrenia. To test this hypothesis, and in an effort to more clearly establish the relationship between peripheral inflammation and schizophrenia, we performed a genome-wide gene expression analysis in peripheral blood mononuclear cells from veterans with a diagnosis of schizophrenia and healthy controls.