Abstract
Schizophrenia (Sz) probably occurs after genetically susceptible individuals encounter a deleterious environmental factor that triggers epigenetic mechanisms to change CNS gene expression. To determine if omnibus changes in CNS gene expression are present in Sz, we compared mRNA levels in the frontal pole (Brodmann’s area (BA) 10), the dorsolateral prefrontal cortex (BA 9) and cingulate cortex (BA 33) from 15 subjects with Sz and 15 controls using the Affymetrix™ Human Exon 1.0 ST Array. Differences in mRNA levels (±≥20%; p < 0.01) were identified (JMP Genomics 5.1) and used to predict pathways and gene x gene interactions that would be affected by the changes in gene expression using Ingenuity Pathway Analysis. There was significant variation in mRNA levels with diagnoses for 566 genes in BA 10, 65 genes in BA 9 and 40 genes in BA 33. In Sz, there was an over-representation of genes with changed expression involved in inflammation and development in BA 10, cell morphology in BA 9 and amino acid metabolism and small molecule biochemistry in BA 33. Using 94 genes with altered levels of expression in BA 10 from subjects with Sz, it was possible to construct an interactome of proven direct gene x gene interactions that was enriched for genes in inflammatory, developmental, oestrogen, serotonergic, cholinergic and NRG1 regulated pathways. Our data shows complex, regionally specific changes in cortical gene expression in Sz that are predicted to affect homeostasis between biochemical pathways already proposed to be important in the pathophysiology of the disorder.
Highlights
Schizophrenia (Sz) is a psychiatric disorder defined by the presence of a constellation of symptoms that includes positive symptoms, negative symptoms and cognitive deficits.[1]
Demographics and sample collection data There were no significant differences in age, gender ratio, postmortem interval (PMI) or central nervous system (CNS) pH between the diagnostic groups (Table 1)
We recently published data reporting changes in gene expression in BA 9 from subjects with Sz,[40] only 10 of the genes with altered levels of expression in BA 9 in our current study were npj Schizophrenia (2018) 4 changes in the activity of pathways involved in cell death and survival in subjects with Sz may extend beyond the CNS, are not due to effects of antipsychotic drug treatment and are not associated with a prolonged duration of illness
Summary
Schizophrenia (Sz) is a psychiatric disorder defined by the presence of a constellation of symptoms that includes positive symptoms (e.g., hallucinations and delusions), negative symptoms (e.g., anhedonia and social withdrawal) and cognitive deficits.[1]. It is increasingly accepted that the disorder occurs in individuals with a genetic predisposition who encounter deleterious environmental factors that trigger functional changes in the central nervous system (CNS).[4] It is understood that in disorders that result from gene and environment interactions, the impact of environment is predominantly through epigenetic mechanisms that act to change gene expression.[5] in Sz, it would be expected that there would be changes in gene expression in regions of the CNS that are dysfunctional in subjects with the disorder. A dysfunctional cortex is recognised as making a major contribution to the pathophysiology of Sz,[6] it would seem likely that changes in cortical gene expression could be contributing to the pathophysiology of the disorder
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