Identification of schizophrenia symptom-related gene modules by postmortem brain transcriptome analysis

Abstract

Schizophrenia is a multifactorial disorder, the genetic architecture of which remains unclear. Although many studies have examined the etiology of schizophrenia, the gene sets that contribute to its symptoms have not been fully investigated. In this study, we aimed to identify each gene set associated with corresponding symptoms of schizophrenia using the postmortem brains of 26 patients with schizophrenia and 51 controls. We classified genes expressed in the prefrontal cortex (analyzed by RNA-seq) into several modules by weighted gene co-expression network analysis (WGCNA) and examined the correlation between module expression and clinical characteristics. In addition, we calculated the polygenic risk score (PRS) for schizophrenia from Japanese genome-wide association studies, and investigated the association between the identified gene modules and PRS to evaluate whether genetic background affected gene expression. Finally, we conducted pathway analysis and upstream analysis using Ingenuity Pathway Analysis to clarify the functions and upstream regulators of symptom-related gene modules. As a result, three gene modules generated by WGCNA were significantly correlated with clinical characteristics, and one of these showed a significant association with PRS. Genes belonging to the transcriptional module associated with PRS significantly overlapped with signaling pathways of multiple sclerosis, neuroinflammation, and opioid use, suggesting that these pathways may also be profoundly implicated in schizophrenia. Upstream analysis indicated that genes in the detected module were profoundly regulated by lipopolysaccharides and CREB. This study identified schizophrenia symptom-related gene sets and their upstream regulators, revealing aspects of the pathophysiology of schizophrenia and identifying potential therapeutic targets.

Editorial: Molecular pathology in psychiatric diseases: frontiers of postmortem brain research

“…This increase is a result of reevaluating the significance of brain pathology in schizophrenia, as the antipsychotic mechanism of action highlights the brain regions such as the midbrain, striatum, limbic system, and cortical tracts involved in the dopamine neurotransmitter system, and progress of structural brain imaging research using CT and MRI, and functional brain imaging research using SPECT and PET. Thus, postmortem brain research on schizophrenia and bipolar disorder is currently very active, and due to recent remarkable technological innovations in the field of basic neuroscience, examinations at the molecular level, such as analysis of mRNA ( 1 ), proteins ( 2 – 4 ) and lipids ( 5 ) expressed in the brain, and brain-specific genomic polymorphisms, such as CNV ( 6 ) and DNA methylation ( 7 ) are rapidly being conducted. Against the background of these multifaceted developments in neuroscience and the ability to perform comprehensive analyses of small amounts of tissue samples, postmortem brain studies on psychiatric disorders have shifted from the traditional role of validating the results obtained in basic neuroscience studies to a more exploratory role of adding new findings and providing feedback for other approaches.…”