Co-expression network of neural-differentiation genes shows specific pattern in schizophrenia

Abstract

BackgroundSchizophrenia is a neurodevelopmental disorder with genetic and environmental factors contributing to its pathogenesis, although the mechanism is unknown due to the difficulties in accessing diseased tissue during human neurodevelopment. The aim of this study was to find neuronal differentiation genes disrupted in schizophrenia and to evaluate those genes in post-mortem brain tissues from schizophrenia cases and controls.MethodsWe analyzed differentially expressed genes (DEG), copy number variation (CNV) and differential methylation in human induced pluripotent stem cells (hiPSC) derived from fibroblasts from one control and one schizophrenia patient and further differentiated into neuron (NPC). Expression of the DEG were analyzed with microarrays of post-mortem brain tissue (frontal cortex) cohort of 29 schizophrenia cases and 30 controls. A Weighted Gene Co-expression Network Analysis (WGCNA) using the DEG was used to detect clusters of co-expressed genes that werenon-conserved between adult cases and controls brain samples.ResultsWe identified methylation alterations potentially involved with neuronal differentiation in schizophrenia, which displayed an over-representation of genes related to chromatin remodeling complex (adjP = 0.04). We found 228 DEG associated with neuronal differentiation. These genes were involved with metabolic processes, signal transduction, nervous system development, regulation of neurogenesis and neuronal differentiation. Between adult brain samples from cases and controls there were 233 DEG, with only four genes overlapping with the 228 DEG, probably because we compared single cell to tissue bulks and more importantly, the cells were at different stages of development. The comparison of the co-expressed network of the 228 genes in adult brain samples between cases and controls revealed a less conserved module enriched for genes associated with oxidative stress and negative regulation of cell differentiation.ConclusionThis study supports the relevance of using cellular approaches to dissect molecular aspects of neurogenesis with impact in the schizophrenic brain. We showed that, although generated by different approaches, both sets of DEG associated to schizophrenia were involved with neocortical development. The results add to the hypothesis that critical metabolic changes may be occurring during early neurodevelopment influencing faulty development of the brain and potentially contributing to further vulnerability to the illness.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-015-0098-9) contains supplementary material, which is available to authorized users.

Genetic correlations among psychiatric and immune-related phenotypes based on genome-wide association data

“…58,90 Another correlated locus within 11q23 (11:118579747-118743772) contained GW hits for multiple autoimmune disorders and is suspected to exert pleiotropic effects through several genes, whose functions include repression of aberrant interferon signaling (DDX6), 91 chemokine signaling between T-helper and B-cells (CXCR5), 92,93 and enzymatic break down of microbial disaccharides (TREH). 94 Notably, functional genomic studies have identified DDX6 as a gene that is perturbed during neuronal differentiation of samples derived from individuals with schizophrenia, 95 and as a peripheral blood marker of cerebrospinal fluid serotonin metabolite levels, 96 supporting its relevance to psychiatric phenotypes.…”

Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility

“…Weighted gene coexpression network analysis (WGCNA) (Zhang and Horvath, 2005) is one such approach that has been utilized successfully to provide new biological insight into gene networks involved in several CNS disorders, including autism (Parikshak et al, 2013), Alzheimer's disease (Miller et al, 2013; Zhang et al, 2013), schizophrenia (Maschietto et al, 2015) and alcoholism (Vanderlinden et al, 2013). Previous studies have utilized coexpression analyses in depressed human post-mortem tissue or mouse stress models to describe interesting network level changes in single brain regions, but the mechanistic role of such changes has not been examined (Chang et al, 2014; Gaiteri and Sibille, 2011; Malki et al, 2015; Malki et al, 2013).…”

Altered expression of a unique set of genes reveals complex etiology of Schizophrenia

“…An immunogenic basis of SCZ etiogenesis had also been brought forward [11,102] although counter to this hypothesis has also been placed which limits the role of immune function related genes as a solo or major factor in SCZ etiology [103]. Also, the involvement of growth, differentiation and survival of neurons in the specific brain regions (Table 3c) [104,105] (also discussed in subsection 'Involvement of the gene set in biological processes and events') and pathways related to apoptosis (Table 3d) [81, 82,106] (also discussed in subsection 'Involvement of the gene set in biological processes and events'), and related to protein synthesis (Table 3e) and degradation (Table 3f) [107,108] has been well documented in the literature (also discussed in subsection 'Involvement of the gene set in biological processes and events'). The linkage of FGF signalling pathway (Table 3c) under neuronal growth, differentiation and survival to SCZ etiology has been corroborated by a freshly published study by Narla et al (2017) who regarded it as a central pathway commanding all other pathways in developing brain strengthening the view that SCZ has a neurodevelopmental etiology [109].…”