Gene expression profiling postmortem dorsolateral prefrontal cortex in schizophrenia
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Murray Cairns
PROVIDER: E-MTAB-8386 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:The dorsolateral prefrontal cortex (DLPFC) is the association area in the anterior part of the frontal lobe and has a crucial role in cognitive functioning and negative symptoms in SZschizophrenia. However, limited information of altered protein networks is available in this region in schizophrenia. We performed a proteomic analysis using single-shot liquid chromatography-tandem mass spectrometry of grey matter of postmortem DLPFC in chronic schizophrenia subjects (n=20) and healthy individuals (n=20) followed by bioinformatic analysis to identify altered protein networks in SZ.
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Project description:Suicide and suicide attempts are complex behaviors that result from the interaction of different factors, including genetic variants that increase the predisposition to suicidal behaviors. Copy number variations (CNVs) are deletions or duplications of a segment of DNA usually larger than one kilobase. These structural genetic changes, although quite rare, have been associated with genetic liability to mental disorders, such as autism, schizophrenia, and bipolar disorder. No genome-wide level studies have been published investigating the potential role of CNVs in suicidal behaviors. Based on single-nucleotide polymorphism array data, we followed the Penn-CNV standards to detect CNVs in 1,608 subjects, comprising 475 suicide and suicide attempt cases and 1,133 controls. Although the initial algorithms determined the presence of CNVs on chromosomes 6 and 12 in seven and eight cases, respectively, compared with none of the controls, visual inspection of the raw data did not support this finding. Furthermore we were unable to validate these findings by CNV-specific real-time polymerase chain reaction. Additionally, rare CNV burden analysis did not find an association between the frequency or length of rare CNVs and suicidal behavior in our sample population. Although our findings suggest CNVs do not play an important role in the etiology of suicidal behaviors, they are not inconsistent with the strong evidence from the literature suggesting that other genetic variants account for a portion of the total phenotypic variability in suicidal behavior.
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Project description:DNA methylation of gene promoter regions represses transcription and is a mechanism via which environmental risk factors could affect cells during development in individuals at risk for schizophrenia. We investigated DNA methylation in patient-derived cells that might shed light on early development in schizophrenia. Induced pluripotent stem cells (iPS cells) may reflect a âground stateâ upon which developmental and environmental influences would be minimal. Olfactory neurosphere-derived cells (ONS cells) are an adult-derived neuro-ectodermal stem cell modified by developmental and environmental influences. Fibroblasts provide a non-neural control for life-long developmental and environmental influences. Genome-wide profiling of DNA methylation and gene expression was done in these three cell types from the same individuals. All cell types had distinct, statistically significant schizophrenia-associated differences in DNA methylation and linked gene expression, with Gene Ontology analysis showing that the differentially affected genes clustered in networks associated with cell growth, proliferation and movement, functions known to be affected in schizophrenia patient-derived cells. Only 5 gene loci were differentially methylated in all three cell types. These findings suggest that schizophrenia-associated DNA methylation may be a response to the homeostatic demands of different cell types in their local environments. Understanding the role of epigenetics in cell function in the brain in schizophrenia is likely to be complicated by similar cell type differences in intrinsic and environmentally-induced epigenetic regulation. This dataset represents the gene expression part of the study. The DNA methylation data is deposited under accession E-MTAB-2154.
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Project description:Despite the growing importance of the cortico-cerebellar-thalamo-cortical circuit in schizophrenia, limited information is available regarding altered molecular networks in cerebellum. To identify altered protein networks, we conducted proteomic analysis of grey matter of postmortem cerebellar cortex in chronic schizophrenia subjects (n=12) and healthy individuals (n=14) followed by an extensive bioinformatic analysis. Two double-hit postnatal stress murine models for SZ were used to validate the most robust candidates.
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Project description:The existence of repressive and durable chromatin assemblies along gene promoters or networks, especially in the brain, is of theoretical and therapeutic relevance in a subset of individuals diagnosed with schizophrenia who experience a chronic, persistent, and treatment-resistant trajectory. We used chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) to generate an epigenomic map that includes differential sites occupied by di-methylated lysine 9 of histone 3 (H3K9me2), a repressive modification that is yet unexplored in human postmortem brain tissue. We have discovered over 150 significantly differential promoter sites in the postmortem prefrontal cortex tissue of individuals diagnosed with schizophrenia (n=15) when compared to controls (n=15). Potentially dysregulated gene categories include postsynaptic proteins, processing enzymes (for proproteins, lipids, and oxidative stress), cadherin family genes, the complement system, and peptide hormones. Ten genes with significantly increased or decreased H3K9me2 promoter occupation were selected through statistical analysis, function, or previous GWAS association, and qRT-PCR was performed on an extended sample of postmortem brain tissue, adding an additional 17 controls, 7 individuals with schizophrenia, and 19 individuals with bipolar samples (n=32 control, 22 schizophrenia, 19 bipolar). This approach revealed that mRNA expression levels correlated with chromatin modification levels in eight of ten selected genes, and mRNA expression in the total sample could be predicted by the occupancy of H3K9me2. Utilization of this method and replication in a larger sample open a pathway to durable and restrictive epigenomic assemblies whose accumulation across the lifespan of individuals diagnosed with schizophrenia may explain treatment resistance, and advance therapeutic options.
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Project description:Gray matter volume in the cerebral cortex has been consistently found to be decreased in patients with schizophrenia. The superior temporal gyrus (STG) is one of the cortical regions that exhibit the most pronounced volumetric reduction. This reduction is generally thought to reflect, at least in part, decreased number of synapses; the majority of these synapses are believed to be furnished by glutamatergic axon terminals onto the dendritic spines on pyramidal neurons. Pyramidal neurons in the cerebral cortex exhibit layer-specific connectional properties, providing neural circuit structures that support distinct aspects of higher cortical functions. For instance, dendritic spines on pyramidal neurons in layer 3 of the cerebral cortex are targeted by both local and long-range glutamatergic projections in a highly reciprocal fashion. Synchronized activities of pyramidal neuronal networks, especially in the gamma frequency band (i.e. 30-100 Hz), are critical for the integrity of higher cortical functions. Disturbances of these networks may contribute to the pathophysiology of schizophrenia by compromising gamma oscillation. This concept is supported by the following postmortem and clinical observations. First, the density of dendritic spines on pyramidal neurons in layer 3 of the cerebral cortex, including the STG, have been shown to be significantly decreased by 23-66% in subjects with schizophrenia. Second, consistent with these findings, the average somal area of these pyramidal cells is significantly smaller. Third, we have recently found that, in the prefrontal cortex, the density of glutamatergic axonal boutons, of which dendritic spines are their major targets, was significantly decreased by as much as 79% in layer 3 (but not layer 5) in subjects with schizophrenia. Finally, an increasing number of clinical studies have consistently demonstrated that gamma oscillatory synchrony is profoundly impaired in patients with schizophrenia. Furthermore, gamma impairment has been linked to the symptoms and cognitive deficits of the illness and the severity of these symptoms and deficits have in turn been associated with the magnitude of cortical gray matter reduction. Taken together, understanding the molecular underpinnings of pyramidal cell dysfunction will shed important light onto the pathophysiology of cortical dysfunction of schizophrenia. In order to gain insight into the molecular determinants of pyramidal cell dysfunction in schizophrenia, we combined LCM with Affymetrix microarray and high-throughput TaqManM-BM-.-based MegaPlex qRT-PCR approaches, respectively, to elucidate the alterations in messenger ribonucleic acid (mRNA) and microRNA (miRNA) expression profiles of these neurons in layer 3 of the STG. We found that transforming growth factor beta (TGFM-NM-2) and BMP (bone morphogenetic proteins) signaling pathways and many genes that regulate extracellular matrix (ECM), apoptosis and cytoskeleton were dysregulated in schizophrenia. In addition, we identified 10 miRNAs that were differentially expressed in this illness; interestingly, the predicted targets of these miRNAs included the dysregulated pathways and gene networks identified by microarray analysis. Together these findings provide a neurobiological framework within which we can begin to formulate and test specific hypotheses about the molecular mechanisms that underlie pyramidal cell dysfunction in schizophrenia. Gene epxression microarray from RNA isolated from pyramidal cells in layer III of the STG from 9 normal controls and 9 subjects with schizophrenia. There was no significant difference between diagnosis groups for age, sex, and post mortem interval (PMI).
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Project description:The primary study aim was to identify long non-coding RNA (lncRNA) abnormalities associated with ultra-high-risk (UHR) for psychosis based on a weighted gene co-expression network analysis.UHR patients were screened by the structured interview for prodromal syndromes (SIPS). We performed a WGCNA analysis on lncRNA and mRNA microarray profiles generated from the peripheral blood samples in fourteen treatment-seeking patients with UHR who never received psychiatric medication and eighteen demographically matched typically developing controls. Gene Ontology (GO) analysis and canonical correlation analysis were then applied to reveal functions and correlation between lncRNAs and mRNAs.The lncRNAs were organized into co-expressed modules by WGCNA, two modules of which were strongly associated with UHR. The mRNA networks were constructed and two disease-associated mRNA modules were identified. A functional enrichment analysis showed that mRNAs were highly enriched for immune regulation and inflammation. Moreover, a significant correlation between lncRNAs and mRNAs were verified by a canonical correlation analysis.We identified novel lncRNA modules related to UHR. These results contribute to our understanding of the molecular basis of UHR from the perspective of systems biology and provide a theoretical basis for early intervention in the assumed development of schizophrenia.
2020-11-30 | E-MTAB-9804 | biostudies-arrayexpress
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Project description:Gene expression is regulated by genetic variants and DNA methylation with evidence from molecular biology studies, as well as expression QTL (eQTL) mapping and methylation QTL (mQTL) mapping. In this study, we explored the interaction between genetic variants and DNA methylation for its influence on gene expression. We analyzed a postmortem brain data and identified 2,768 SNP-methylation interaction (SMI) that can survive Bonferroni correction for the number of tests in cis- region of each gene. Seven SNP-methylation pairs were significant after Bonferroni correction for all the tests, including number of gene expression traits, we performed in this study. Only a small proportion of the SMI had evidence from the exact same SNP-transcript pair in eQTL mapping or SNP-methylation pair in mQTL mapping. This suggested that the interaction analysis could uncover novel regulatory relationships, which would be missed by eQTL or mQTL analyses. Since methylation per se is regulated by both genetic and environmental factors, analysis indicates that the SMI detected in this study may involve both genetic and environmental regulation. A total of 155 postmortem cerebellum brains were used in this study, including 47 bipolar disorder, 46 schizophrenia, 15 depression patients and 47 normal controls. All were of European Ancestry. We also designed 13 random replicates in our experiment. Illumina Infinium HumanMethylation27 BeadChip was used for DNA methylation profiling. The assay was performed at the Genomics Core Facility at Northwestern University.
2013-06-30 | E-GEOD-38873 | biostudies-arrayexpress
Project description:Schizophrenia: postmortem dorsal lateral prefrontal cortex (DLPFC)
| PRJNA343829 | ENA