Gene expression analysis reveals schizophrenia-associated dysregulation of immune pathways in peripheral blood mononuclear cells

Abstract

Peripheral blood mononuclear cells (PBMCs) represent an accessible tissue source for gene expression profiling in schizophrenia that could provide insight into the molecular basis of the disorder. This study used the Illumina HT_12 microarray platform and quantitative real time PCR (QPCR) to perform mRNA expression profiling on 114 patients with schizophrenia or schizoaffective disorder and 80 non-psychiatric controls from the Australian Schizophrenia Research Bank (ASRB). Differential expression analysis revealed altered expression of 164 genes (59 up-regulated and 105 down-regulated) in the PBMCs from patients with schizophrenia compared to controls. Bioinformatic analysis indicated significant enrichment of differentially expressed genes known to be involved or associated with immune function and regulating the immune response. The differential expression of 6 genes, EIF2C2 (Ago 2), MEF2D, EVL, PI3, S100A12 and DEFA4 was confirmed by QPCR. Genome-wide expression analysis of PBMCs from individuals with schizophrenia was characterized by the alteration of genes with immune system function, supporting the hypothesis that the disorder has a significant immunological component in its etiology.

Fig. 1

Volcano plot of differentially expressed genes. A scatter-plot of the log odds (probability) against the log₂ fold change in expression in PBMCs (schizophrenia/control). Genes with statistically significant differential expression in schizophrenia (Benjamini–Hochberg corrected p < 0.05, fold change >10% up or down-regulation) with current NCBI Entrez gene records are depicted in the upper quadrants; 105 genes down-regulated on the left (green) and 59 genes up-regulated on the right (red). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

A QPCR validation of differentially expressed genes. The expression of ten genes highlighted by the microarray was analyzed by QPCR. Bars indicate mean fold change + SEM for 83 participants: 48 schizophrenia or schizoaffective patients and 35 non-psychiatric controls. The control cohort is set at 1. Differential expression of EIF2C2, EVL, DEFA4, S100A12 (*p < 0.05) and PI3 and MEF2D (**p < 0.01) was validated, with a further two genes (CCR7 p = 0.054; CD6 p = 0.053) showing a non-significant trend in the same direction as the microarray data. B Fold changes and p values for each gene on the microarray and the QPCR (one tailed student's t-test) are shown.

Fig. 3

Functional annotations of differentially expressed genes by category. Assortment of functional annotations by broad functional categories revealed over-representation of genes with immune and inflammation-related functions (∼37%) in the list of genes differentially expressed between schizophrenia and controls.