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Co-expression network analysis from genes involved with neural-differentiation shows specific pattern in patients with schizophrenia

ABSTRACT: Schizophrenia is a severe and debilitating neuropsychiatric disorder with the involvement of genetic and environmental factors contributing to its pathogenesis. The specific role of the brain cell types in the disease remains uncovered due to the difficulties in accessing diseased tissue. This study analysed molecular alterations in human induced pluripotent stem cells (hiPSCs) derived from fibroblasts from control subject and individual with schizophrenia and further differentiated to neuron to identify genes relevant for the development of schizophrenia. We identified 228 genes that are involved with metabolic processes, signal transduction, nervous system development, regulation of neurogenesis and neuronal differentiation. These genes were analysed in expression microarrays of post-mortem brain tissue (frontal cortex) of additional patients with schizophrenia and normal individuals revealing only six common genes: CACNA1E, CEBPB, DUX4, EDNRA, SPHK1 and SPRY4 (GSE62191). Furthermore, a co-expression network analysis of the 228 genes revealed a non-conserved module enriched for genes associated with oxidative stress and negative regulation of cell differentiation as involved with schizophrenia. This study supports the relevance of using cellular approaches to dissect molecular aspects of neurogenesis with impact in the schizophrenic brain.

ORGANISM(S): Homo sapiens

PROVIDER: GSE62105 | GEO | 2014/10/09

SECONDARY ACCESSION(S): PRJNA263379

REPOSITORIES: GEO

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Co-expression network analysis from genes involved with neural-differentiation shows specific pattern in patients with schizophrenia

Project description:Schizophrenia is a severe and debilitating neuropsychiatric disorder with the involvement of genetic and environmental factors contributing to its pathogenesis. The specific role of the brain cell types in the disease remains uncovered due to the difficulties in accessing diseased tissue. This study analysed molecular alterations in human induced pluripotent stem cells derived from fibroblasts from control subject and individual with schizophrenia and further differentiated to neuron to identify genes relevant for the development of schizophrenia. We identified 228 genes that are involved with metabolic processes, signal transduction, nervous system development, regulation of neurogenesis and neuronal differentiation. These genes were analysed in expression microarrays of post-mortem brain tissue (frontal cortex) of additional patients with schizophrenia and normal individuals revealing only six common genes: CACNA1E, CEBPB, DUX4, EDNRA, SPHK1 and SPRY4. Furthermore, a co-expression network analysis of the 228 genes revealed a non-conserved module enriched for genes associated with oxidative stress and negative regulation of cell differentiation as involved with schizophrenia. This study supports the relevance of using cellular approaches to dissect molecular aspects of neurogenesis with impact in the schizophrenic brain. Biopsies of primary human fibroblasts from a 48-year-old woman with DSM-IVTR schizophrenia defined as treatment-resistant under clozapine treatment (SZCP) were collected in parallel with a control subject (CON) negative for any major lifetime DSM-IVTR diagnosis. Fibroblasts underwent primary culture procedures to generate hiPSCs and were subsequently differentiated into neurons (NPC). Samples generation and culture conditions are described in Paulsen et al. (2011). Five replicates of expression microarray experiments using a reference design, where test sample (NPC) is derived from reference sample (hiPSC).

2014-10-09 | E-GEOD-62105 | biostudies-arrayexpress

Comparison of post-mortem tissue from brain BA10 region between schizophrenic and control patients.

Project description:Analysis of gene expression in two large schizophrenia cohorts identifies multiple changes associated with nerve terminal function. Schizophrenia is a severe psychiatric disorder with a world-wide prevalence of 1%. The pathophysiology of the illness is not understood, but is thought to have a strong genetic component with some environmental influences on aetiology. To gain further insight into disease mechanism, we used microarray technology to determine the expression of over 30 000 mRNA transcripts in post-mortem tissue from a brain region associated with the pathophysiology of the disease (Brodmann area 10: anterior prefrontal cortex) in 28 schizophrenic and 23 control patients. Post-mortem derived BA10 tissue from 28 schizophrenic and 23 control patients were compared. Age, gender, post-mortem delay and pH of brain lysates data were also captured.

2009-08-13 | E-GEOD-17612 | biostudies-arrayexpress

Comparing Control and Schizophrenic hiPSC-derived Neurons

Project description:Schizophrenia is a debilitating neurological disorder for which no cure exists. Few defining characteristics of schizophrenic neurons have been identified and the molecular mechanisms responsible for schizophrenia are not well understood, in part due to the lack of patient material for study. Human induced pluripotent stem cells (hiPSCs) offer a new strategy for studying schizophrenia. We have created the first cell-based human model of a complex genetic psychiatric disease by generating hiPSCs from schizophrenic patients and subsequently differentiating these cells to hiPSC-derived neurons in vitro. Schizophrenic hiPSC-derived neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression. Gene expression profiles of schizophrenic hiPSC-derived neurons identified altered expression of many components of the cAMP and WNT signaling pathways. Key cellular and molecular elements of the schizophrenic phenotype were ameliorated following treatment of schizophrenic hiPSC-derived neurons with the antipsychotic loxapine. 3 independent differentiations (biological replicates) for each of four control and four schizophrenic patients were analyzed.

2011-05-01 | E-GEOD-25673 | biostudies-arrayexpress

Epigenome analysis of normal and schizophrenic samples

Project description:We analyzed fresh frozen post-mortem brain tissue from a cohort of 73 schizophrenic and 52 control samples, using the Illumina Infinium HumanMethylation450 Bead Chip, to investigate genome-wide DNA methylation patterns in patients diagnosed with schizophrenia.

2019-03-21 | GSE128601 | GEO

Comparing Control and Schizophrenic hiPSC-derived Neurons

2011-05-01 | GSE25673 | GEO

Comparison of post-mortem tissue from Brodman Brain BA22 region between schizophrenic and control patients

Project description:Transcriptional analysis of the superior temporal cortex (BA22) in schizophrenia: Pathway insight into disease pathology and drug development Schizophrenia is a highly debilitating psychiatric disorder which is known to have heritable genetic and environmental components. To gain some insight into the mechanisms underpinning both positive and negative symptoms of the disease, we determined the genome wide expression of mRNA transcripts in post-mortem tissue from the superior temporal cortex (Brodmann Area 22, BA22) in schizophrenic and control patients. The BA22 region is known to mediate the positive pathophysiology of schizophrenia; we compared this to the anterior prefrontal cortex (BA10) from the same subjects, which is known to mediate negative symptoms. Following adjustments for confounding clinical, sample and experimental sources of variation, we carried out gene set enrichment analysis in each region using pathway data. We identified an over-representation of genes involved in cytoskeletal remodelling, neurodevelopment, cell adhesion, cellular signalling, neurotransmission and autophagy. Collectively our analysis indicates a disruption of processes underpinning synaptic plasticity in both regions. Region-specific changes support the dysregulation of distinct pathways in the BA10 and BA22 regions. This may highlight new therapeutic opportunities to treat both negative and positive symptoms of the disease. Post-mortem derived BA22 tissue from schizophrenic and control patients were compared. Age, gender, post-mortem delay and pH of brain lysates data were also captured.

2011-12-31 | E-GEOD-21935 | biostudies-arrayexpress

Using the expression profile of peripheral blood to investigate regulatory pathways in schizophrenia

Project description:Schizophrenia is best considered a “two-hit” disease, with a neurodevelopment impairment followed by an additional process in early adulthood. Both are regulated by hormonal (like thyroid and retinols) and signal transduction pathways (like WNT), which in turn have been previously identified in post-mortem brain studies of schizophrenic individuals. While brain studies are fitted for pathology assessment, there are not suitable for searches of a “diagnostic signature” of schizophrenia. In contrast, peripheral blood is easily accessible, and can be used for the study of disease pathways and potentially diagnosis markers. Blood from twenty eight males with DSM-IV schizophrenia under three drug regimens (clozapine, risperidone or haloperidol), and from 10 healthy controls was studied in a microarray platform with 1364 genes belonging to hormonal and signal transduction pathways. Seven genes were differentially expressed between controls and patients with different treatments, and 28 between healthy controls and specific treatments, with four (CTNNA1, GSTM3, HOXA-13 and KRT18) altered in all analyses. While none of these genes has been previously reported in schizophrenia brain studies, many belong to pathways altered in schizophrenia, belonging to chromosomal loci linked to the disease, which warrants additional replication studies to be performed in larger samples.

2012-06-22 | GSE19112 | GEO

Comparison of post-mortem tissue from brain BA10 region between schizophrenic and control patients.

2009-08-13 | GSE17612 | GEO

Gene expression in human post-mortem brain samples from schizophrenic subjects and matched controls

Project description:This laboratory focuses on the molecular mechanisms of neuropsychiatric and neurodegenerative disorders Gene expression patterns from the pefrontal cortical region (Brodmann Area 46) of subjects with schizophrenia and age- and sex-match control subjects was analyzed. The prefrontal cortex was chosen since it is a primary brain region implicated in the pathophysiological of schizophrenia. Furthermore, this region was used in our previous proteomics studies, allowing for the direct comparison of changes in protein levels to gene expression results. 16 schizophrenic subjects were studied, consisting of 8 subjects with duration of illness (DOI) < 5 years and 8 subjects with DOI > 22 years. 16 age- and sex-matched controls were also studied. Gene expression profiles were analyzed from individual subjects; a total of 32 samples were hybridized to the custom designed CFG GLYCOv2 glycogene array.

2011-02-17 | E-GEOD-27356 | biostudies-arrayexpress

Expression data from rat prefrontal cortex administrated with MK-801

Project description:Schizophrenia is a group of severe mental disorders. MK-801 is a common chemical that is used to construct schizophrenic animal model. In the present study, male SD rats were received MK-801 (0.2 mg/kg) intraperitoneal injections for 2 weeks. PFC tissue samples were collected freshly when sacrificing the rats and then quickly frozen and stored under -80°C for RNA sequencing. Differentially-expressed genes (DEGs) were determined by using DESeq2. A total of 129 DEGs, including 50 down-regulated and 79 up-regulated DEGs, were determined. By comparing with the online database TargetScanHuman (Release 8.0) and miRDB (Version 6.0), we found 4 genes (SIK1, TWIST1, BTG2, EGR2) that were altered in the schizophrenic model rat PFC and also are potential targets of miR-25.

2023-01-09 | GSE220510 | GEO

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