Background: Due to the heterogeneous nature of schizophrenia, understanding the genetic risk for the disease is a complex task. Gene expression studies have proven to be more reliable than association studies as they are consistently replicated in a tissue specific manner. Methods: Using RNA-Seq we analysed gene expression in the frontal cortex of 24 individuals with schizophrenia and 25 unaffected controls. Results: We identified 1146 genes that were differentially expressed in schizophrenia, approximately 60% of which were up-regulated and 366 of 1146 (32%) also have aberrant DNA methylation (p = 2.46 Chi 10(-39)). The differentially expressed genes were significantly overrepresented in several pathways including inflammatory (p = 8.7 Chi 10(-3)) and nitric oxide pathways (p = 9.2 Chi 10(-4)). Moreover, these genes were significantly enriched for those with a druggable genome (p = 0.04). We identified a number of genes that are significantly up-regulated in schizophrenia as confirmed in other gene expression studies using different brain tissues. Of the 349 genes associated with schizophrenia from the Psychiatric Genomics Consortium we identified 16 genes that are significant from our list of differentially expressed genes. Conclusions: Our results identified biological functional genes that are differentially expressed in schizophrenia. A subset of these genes are clinically proven drug targets. We also found a strong pattern of differentially expressed immune response genes that may reflect an underlying defect in schizophrenia. Crown Copyright (C) 2016 Published by Elsevier Inc. All rights reserved.