The association between schizophrenia and the immune system: Review of the evidence from unbiased 'omic-studies'.

A role for immune processes in the pathogenesis of schizophrenia has been suggested by genetic and epidemiological studies, as well as cross-sectional studies on blood and brain samples. However, results are heterogeneous, which is likely caused by low samples sizes, insufficient control of confounders that influence immune processes, and potentially publication bias. Large hypothesis-free 'omic' studies partially circumvent these problems and could provide further evidence for a role of immune pathways in schizophrenia. In this review we assessed whether the largest genome, transcriptome and methylome studies in schizophrenia to date support a link with the immune system. We constructed an overview of the schizophrenia-associated genes and transcripts that were identified in these large 'omic' studies. We then performed a hypothesis-driven analysis to examine the association and enrichment of immune system-related genes and transcripts in these datasets. Additionally, we reviewed secondary analyses that were previously performed on these 'omic' studies. Except for the link between complement factor 4 (C4), we found limited evidence for a role of microglia and immune processes among genetic risk variants. Transcriptome and methylome studies point towards alterations in immune system related genes, pathways and cells. This includes changes in microglia, as well as complement, nuclear factor-κB, toll-like receptor and interferon signaling pathways. Many of these associated immune-related genes and pathways have been shown to be involved in neurodevelopment and neuronal functioning. Additional replication of these findings is needed, but once further conformation is provided, these findings could be a potentially interesting target for future therapies.