A Genetics Perspective on the Role of the (Neuro)Immune System in Schizophrenia

Abstract

The immune system has long been hypothesized to play a role in schizophrenia pathogenesis based on data from diverse disciplines. Recent reports of the identification of schizophrenia-associated genetic variants and their initial biological characterization have renewed investigation of the role of the immune system in schizophrenia. In the current review, the plausibility of a role of the immune system in schizophrenia pathogenesis is examined, by revisiting epidemiology, neuroimaging, pharmacology, and developmental biology from a genetics perspective, as well as by synthesizing diverse findings from the emerging and dynamic schizophrenia genomics field. Genetic correlations between schizophrenia and immunological disorders are inconsistent and often contradictory, as are neuroimaging studies of microglia markers. Small therapeutic trials of anti-inflammatory agents targeting immune function have been consistently negative. Some gene expression analyses of post-mortem brains of patients with schizophrenia have reported an upregulation of genes of immune function though others report downregulation, and overall transcriptome profiling to date does not support an upregulation of immune pathways associated with schizophrenia genetic risk. The currently reviewed genetic data do not converge to reveal consistent evidence of the neuroimmune system in schizophrenia pathogenesis, and indeed, a substantive role for the neuroimmune system in schizophrenia has yet to be established.

Keywords: Gene expression; Genetics; Human brain; Immunity; Inflammation; Schizophrenia.

Figure 1:. Gene Expression Trajectory of Immune Genes and MHC Region Genes, LIBD BrainSeq DLPFC

Notes: -Gene Expression is DLPFC LIBD BrainSeq (Described in Jaffe et al., Nature Neuroscience, 2018), n=54 fetal, n=284 post-natal samples -Plot is first principal component of (A) Immune Gene Expression (n=515) and (B) MHC Gene Expression (n=143), RPKM Threshold of 0.1 for gene inclusion −y-axis is gene expression adjusted for quality surrogate variables (as per Jaffe et al, (2017) to control for RNA degradation, hidden confounders) −x-axis is age, Pre-natal on left pane and Post-natal on right pane −Blue colored line is LOESS fit line As per Birnbaum et al., (Molecular Psychiatry, 2018), genes within the following pathways are included in the ‘Immune Gene Set’ (n=515) with RPKM>0.1 −Adaptive: T-Cell Receptors, B-cell Receptors, Regulatory T Cells, Cytotoxic T cells -Innate: Microglia, NK Cell cytotixicity, Complement, Innate Immune Receptors, Oxidative Stress -Cytokine: Interleukins, Chemokines, TNF, TGF-Beta, and Interferon Signaling -Other Immune sets includes: NF-KB, Heat Shock Proteins, Blood Brain Barrier, Nuclear Receptors, and Eicosanoids