Blood methylomes of schizophrenia patients differing in their response to risperidone treatment
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Ana Lokmer
PROVIDER: E-MTAB-11921 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:This SuperSeries is composed of the following subset Series: GSE38481: A gene co-expression network in whole blood of schizophrenia patients is independent of antipsychotic-use and enriched for brain-expressed genes [HumanRef-8 v3.0] GSE38484: A gene co-expression network in whole blood of schizophrenia patients is independent of antipsychotic-use and enriched for brain-expressed genes [HumanHT-12 V3.0] Refer to individual Series
2012-07-08 | E-GEOD-38485 | biostudies-arrayexpress
Project description:Antipsychotics are the main line of treatment for schizophrenia, despite being effective only in about 50% of patients. Additionally, serious side effects may cause medication drop-out, aggravated by a lack of understanding about how these drugs act at molecular level. As proteomics is a suitable tool for studying multifactorial disorders, the main goal was to unravel signaling pathways in blood plasma associated with a positive treatment outcome for the atypical antipsychotics olanzapine and risperidone. Blood plasma was collected from schizophrenia patients six weeks after treatment (T6), and patients were classified as good or poor responders to olanzapine or risperidone, and then samples were compared to each patient's baseline (T0). All samples were analyzed using label-free quantitative shotgun proteomics. Samples were depleted of the 14 most abundant proteins in plasma, were digested, and then submitted to M-Class two-dimensional nano-liquid chromatography, coupled online to a Synapt G2-Si mass spectrometer. Data was obtained in MSE mode (data- independent acquisition) in combination with ion-mobility (HDMSE). The proteins found to be differentially abundant in good responders compared to poor responders for risperidone and olanzapine were functionally analyzed in silico using Ingenuity® Pathway Analysis and were found to be mostly involved with immune system functions. This data can contribute to better understand the biochemical signaling peripherally triggered by antipsychotic medication, and can eventually be used to help improve treatment outcome by predicting patient response as well as through the development of new medication or a combination of drugs that act on the immune system to reduce the duration of poor response periods in patients suffering with schizophrenia.
2020-06-01 | PXD015049 | Pride
Project description:Background. Schizophrenia is an idiopathic psychiatric disorder with a high degree of polygenicity. Evidence from genetics, single-cell, and pharmacological studies suggest an important overlap between genes involved in the etiology of schizophrenia and the cellular mechanisms of action of antipsychotics in medium spiny neurons (MSNs). Methods. We applied single-cell RNA-sequencing to striatal samples from C57BL/6J mice chronically exposed to a typical antipsychotic (haloperidol), an atypical antipsychotic (olanzapine), or placebo. We implemented careful statistical analyses to identify differentially expressed genes in two cell populations identified from the single-cell RNA-sequencing (MSNs and microglia) and applied multiple analysis pipelines to contextualize these findings. Results. Differential expression analysis showed that there was a larger share of differentially expressed genes (DEGs) in MSNs from mice treated with olanzapine vs. haloperidol. DEGs were enriched in broad loci implicated by genetic studies of schizophrenia, and we highlighted nine genes with convergent evidence. Pathway analyses highlighted alternative splicing, mitochondrial function, and neuron and synapse development as particularly engaged by antipsychotics. In microglia, we identified pathways involved in microglial activation and inflammation as part of the antipsychotic response. Conclusions. Our goal was to evaluate connections between schizophrenia genetic findings and cellular gene expression changes following antipsychotic exposure. We found that differential gene expression in MSNs from mice chronically treated with olanzapine converges on similar pathways and gene sets.
2021-04-14 | GSE171977 | GEO
Project description:Multiple studies have shown that brain gene expression is disturbed in subjects suffering from schizophrenia. However, disentangling disease effects from alterations caused by neuroleptics is a challenging task. <br> To address the issues of disease heterogeneity and the effect of antipsychotic medication, we use a large collection of 110 brain autopsy samples, subdivided according to the type of antipsychotic medication received. We use global and high-resolution mRNA quantification techniques to analyse gene expression in brain tissues. We also analyse transcription in-vitro, in cell lines before and after treatment with cytokines.<br> Results. We show that inflammation-related genes are up regulated in all groups of patients, including those not treated at the time of death. In particular, four co-expressed genes that are inducible by inflammatory cytokines showed increased mRNA levels, namely IFITM2, IFITM3, SERPINA3, and GBP1 (p-values from qPCR ? 0.01). We also show that these genes are expressed in oligodendrocyte and endothelial cell lines, and transcription is inducible by inflammatory cytokines in both cell lines. Our results give molecular support to the inflammatory theory of schizophrenia and suggest that inflammatory cytokines may stimulate transcription in endothelial brain cells during schizophrenia progression. Unexpectedly, inflammation-related genes may also have a role in myelin producing cells, since they are also inducible by cytokines in oligodendrocyte cell lines. Our findings encourage future research to explore whether anti-inflammatory agents can be used in combination with traditional antipsychotics for a more efficient treatment of schizophrenia.
2007-12-06 | E-MEXP-857 | biostudies-arrayexpress
Project description:While the pathophysiology of schizophrenia has been extensively investigated using homogenized postmortem brain samples, few studies have examined changes in brain samples with techniques that may attribute perturbations to specific cell types. To fill this gap, we performed microarray assays on mRNA isolated from anterior cingulate cortex (ACC) superficial and deep pyramidal neurons from 12 schizophrenia and 12 control subjects using laser capture microdissection. Among all the annotated genes, we identified 134 significantly increased and 130 decreased genes in superficial pyramidal neurons, while 93 significantly increased and 101 decreased genes were found in deep pyramidal neurons, in schizophrenia compared to control subjects. In these differentially expressed genes, we detected lamina-specific changes of 55 and 31 genes in superficial and deep neurons in schizophrenia, respectively. Gene set enrichment analysis (GSEA) was applied to the entire pre-ranked differential expression gene lists to gain a complete pathway analysis throughout all annotated genes. Our analysis revealed over-represented groups of gene sets in schizophrenia, particularly in immunity and synapse related pathways in pyramidal neurons, suggesting the disruption of these pathways plays an important role in schizophrenia. We also detected other pathways previously demonstrated in schizophrenia pathophysiology, including cytokine and chemotaxis, post-synaptic signaling, and glutamatergic synapses. In addition, we observed several novel pathways, including ubiquitin-independent protein catabolic process. We also used a bioinformatics approach to compare our differential expression gene profiles with 51 antipsychotic treatment datasets, demonstrating that our results were not influenced by antipsychotic treatment. Taken together, we found pyramidal neuron-specific changes in neuronal immunity, synaptic dysfunction, and olfactory dysregulation in schizophrenia, providing new insights for the cell-subtype specific pathophysiology of chronic schizophrenia.
2020-02-20 | GSE145554 | GEO
Project description:In pevious research we have shown that the disruption of the normal development of the ventral hippocampus in rodents leads to cellular abnormalities in the frontal cortex and behavioral deficits related to schizophenia (Neurotox Res. 2002, 4(5-6):469-475). We propose the use of gene expression analysis to investigate the molecular underpinnings of these processes which may shed light on the molecular processes relevant to human schizophrenia. In addition, we seek to characterize expression differences induced by chronic administration of antipsychotic medications, which may give insight into the molecular processes involved in ameliorating psychotic symptoms. Using both surgical and drug interventions, we aim to examine experimentally induced expression differences in the rodent brain that are relevant to human neuropsychiatric disorders. Disruption of the normal development of the vental hippocampus or chronic neuroleptic administration, will result in gene expression changes in the frontal cortex of rats. Elucidation of the molecular cascades underlying these treatments will shed light on both the pathoetiology (from the lesion experiments) and theurapeutic processes (from the antipsychotic treatment experiments) involved in human schizophrenia. We have developed 3 groups of samples:; 1] Ventral hippocampal lesion in neonatal rats (treatment and controls, total N=22); 2] Tetrodotoxin disruption of the ventral hippocampus (treatment and controls, total N=20); 3] Chronic administration of neuroleptics (multiple drugs, multiple doses, and controls, total N=63) Grand Total N=105
2008-06-12 | E-GEOD-4031 | biostudies-arrayexpress
Project description:Abnormal N-methyl-D-aspartate receptor (NMDAR) function has been implicated in the pathophysiology of schizophrenia. D-serine is an important NMDAR modulator, and to elucidate the role of the D-serine synthesis enzyme serine racemase (Srr) in schizophrenia, we identified and characterized mice with an ENU-induced mutation that results in a complete loss of Srr activity and drastically reduced D-serine levels. Mutant mice displayed behaviors relevant to schizophrenia, including impairments in prepulse inhibition, sociability and spatial discrimination. Behavioral deficits were rescued by D-serine and the atypical antipsychotic clozapine, and were conversely, amplified by NMDAR inhibition. Expression profiling revealed that the Srr mutation influenced several genes that have been linked to schizophrenia and cognitive ability. Furthermore, analysis of Srr genetic variants in humans identified a robust association with schizophrenia. This study demonstrates that aberrant serine racemase function and diminished D-serine may contribute to schizophrenia pathogenesis, and that D-serine may be a beneficial form of treatment Keywords: genetic-mutant vs. wildtype comparison
2009-09-05 | GSE13974 | GEO
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
Project description:Healthcare workers were recruited at St Bartholomew’s Hospital, London, UK in the week of lockdown in the United Kingdom (between 23rd and 31st March 2020). Participants underwent weekly evaluation using a questionnaire and biological sample collection (including serological assays) for up to 16 weeks when attending for work and self-declared as fit to attend work at each visit, with further follow up samples collected at 24 weeks. Blood RNA sequencing data was to be used to identify host-response biomarkers of early SARS-CoV-2 infection, to evaluate existing blood transcriptomic signatures of viral infection, and to describe the underlying biology during SARS-CoV-2 infection. This submission includes a total of 172 blood RNA samples from 99 participants. Of these, 114 samples (including 16 convalescent samples collected 6 months after infection) were obtained from 41 SARS-CoV-2 cases, with the remaining 58 from uninfected controls. Participants with available blood RNA samples who had PCR-confirmed SARS-CoV-2 infection during follow-up were included as ‘cases’. Those without evidence of SARS-CoV-2 infection on nasopharyngeal swabs and who remained seronegative by both Euroimmun anti S1 spike protein and Roche anti nucleocapsid protein throughout follow-up were included as uninfected controls. ‘Cases’ include all available RNA samples, including convalescent samples at week 24 of follow-up for a subset of participants. For uninfected controls, we included baseline samples only. Sample class denotes weekly interval to positive SARS-CoV-2 PCR; non-infected controls (NIC); convalescent samples (Conv)_.
2021-07-07 | E-MTAB-10022 | biostudies-arrayexpress
Project description:We have previously demonstrated functional and molecular changes in hippocampal subfields in individuals with schizophrenia (SZ) psychosis associated with hippocampal excitability. In this study, we use RNA-seq and assess global transcriptome changes in the hippocampal subfields, DG, CA3, and CA1 from individuals with SZ psychosis and controls to elucidate subfield-relevant molecular changes. We also examine changes in gene expression due to antipsychotic medication in the hippocampal subfields from our SZ ON- and OFF-antipsychotic medication cohort. We identify unique subfield-specific molecular profiles in schizophrenia postmortem samples compared to controls, implicating astrocytes in DG, immune mechanisms in CA3, and synaptic scaling in CA1. We show a unique pattern of subfield-specific effects by antipsychotic medication on gene expression levels with scant overlap of genes differentially expressed by SZ disease effect versus medication effect. These hippocampal subfield changes could provide the basis for previously observed hippocampal SZ pathology and explain the lack of full efficacy of conventional antipsychotic medication on SZ symptomatology. With further characterization, the identified distinct molecular profiles of the DG, CA3, and CA1 in SZ psychosis may serve to identify potential hippocampal-based therapeutic targets.
2020-05-11 | GSE138082 | GEO