Brain Gene Expression Pattern of Subjects with Completed Suicide and Comorbid Substance Use Disorder
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PROVIDER: PRJNA517158 | ENA |
REPOSITORIES: ENA
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Project description:Background/aimAlthough individuals with substance use disorder (SUD) are at high risk of committing suicide, most studies of postmortem gene expression exclude subjects with SUD due to the potential confounding effect of drugs in the transcriptome. Thus, little is known about the gene expression profile in suicides with SUD. The identification of altered biological processes in suicides with SUD is crucial in the comprehension of the interaction between both pathologies.MethodsWe evaluated the gene expression profile in the dorsolateral prefrontal area of suicides and nonsuicides with and without SUD by microarrays.ResultsWe identified 222 differentially expressed genes, predominately enriched in cell proliferation in the comparison between suicides with and without SUD. When comparing the transcriptome of suicides with SUD to nonsuicides with SUD, we identified 550 differentially expressed genes, mainly enriched in oxidative phosphorylation. Differentially expressed genes (1,417) between suicides and nonsuicides without SUD were detected. Most of them were related to mitochondrial function.ConclusionInteraction between suicide and SUD seems to influence the expression of genes involved in glial proliferation and glutamatergic neurotransmission. These results highlight, for the first time, that suicides with SUD have a gene expression profile distinct from that of subjects with only one of these disorders.
| S-EPMC6465692 | biostudies-literature
Project description:We compared the gene expression profile in the dorsolateral prefrontal area of subjects with dual diagnosis who died by suicide to the transcriptome of subjects with mood disorders and subjects with substance use disorder who died by suicide.
2019-12-02 | GSE125681 | GEO
Project description:Background: Major Depressive Disorder (MDD) represents a major social and economic health issue and constitutes a major risk factor for MDD suicide. The molecular pathology of suicidal depression remains poorly understood, although it has been hypothesized that regulatory genomic processes are involved in the pathology of both MDD and suicidality. Methods: Genome-wide patterns of DNA methylation were assessed in depressed MDD suicide completers (n=20) and compared to non-psychiatric, sudden-death controls (n=20) using tissue from two cortical brain regions (Brodmann Area 11 (BA11) and Brodmann Area 25 (BA25)). Analyses focussed on identifying differentially methylated regions (DMRs) associated with suicidal depression, and epigenetic variation was explored in the context of polygenic risk scores for major depression and MDD suicide. Weighted gene co-methylation network analysis was used to identify modules of co-methylated loci associated with depressed MDD suicide completers and polygenic burden for MDD and MDD suicide attempt. Results: We identified a DMR upstream of the PSORS1C3 gene, subsequently validated using bisulfite-pyrosequencing and replicated in a second set of MDD suicide samples, which is characterized by significant hypomethylation in both cortical brain regions in MDD MDD suicide cases. We also identified discrete modules of co-methylated loci associated with polygenic risk burden for MDD suicide attempt, but not major depression. MDD suicide-associated co-methylation modules were enriched among gene networks implicating biological processes relevant to depression and suicidality, including nervous system development and mitochondria function. Conclusions: Our data suggest there are coordinated changes in DNA methylation associated with MDD suicide that may offer novel insights into the molecular pathology associated with depressed MDD suicide completers.
2016-11-01 | GSE88890 | GEO
Project description:We analyzed the levels of DNA methylation in DNA purified from BA9 of 21 depressed suicide completers and 21 healthy controls, using the Infinium® MethylationEPICBeadChip. The goal of the study was to determine which genes were differentially methylated in neurons between the two groups. We identified1,236 differentially methylated CpGs with a p ≤ 0.001. Gene Ontology and Ingenuity Pathway Analysis were performed to determine classes of genes and pathways associated with the suicide completers.
2022-08-26 | GSE156996 | GEO
Project description:A total of 36 postmortem brain samples (23 suicide completers, 13 control sudden death) were collected. We evaluated the proteome profile in the prefrontal cortex (Brodmann area 9, 10) with TMT-based quantification using LC-MS/MS. Several bioinformatics tools were used to elucidate biological mechanisms related to suicide. Subgroup analysis was conducted to find common differentially expressed proteins (DEPs) among various clinically different groups. Among the 9801 proteins identified in our dataset, 295 proteins were differentially expressed between suicide completers and sudden death subjects. Various bioinformatics analysis revealed that suicide completion is predominately enriched in synaptic functions and synaptogenesis especially in endocannabinoid and GABA signaling pathway. Our finding presents the largest protein pools related to suicide completion, and suggests that newly emerging neurotransmitter systems such as endocannabinoid system and synaptogenesis processes may have an impact upon the biological cascade leading to suicide.
2022-05-20 | PXD029845 | Pride
Project description:Ex vivo large-scale proteomic analysis using LC-MS/MS in postmortem brains of patients with substance use disorder and controls. Brain tissue was collected postmortem after consent from the next of kin. As part of the clinical information, medical records were obtained and a detailed psychological autopsy was performed on all participants by interviewing the next-of-kin. Information regarding the psychiatric clinical phenotypes (evidence of depression, mania, and psychosis) stressful life events, age of drug use onset, types of drugs used, smoking and drinking history, and any co-morbidities, was obtained. A diagnosis of substance use disorder was confirmed based on the psychological autopsy, detailed medical records, and review of all relevant case information by three psychiatrists at a consensus meeting. The cause of death was obtained from the medical examiner’s report and toxicological findings after death.
2021-09-10 | PXD025269 | Pride
Project description:Methamphetamine and Other Substance Use Disorder Genetics in Thailand
| PRJNA955367 | ENA
Project description:Background: TrkB-T1 is a BDNF receptor lacking a tyrosine kinase domain that is highly expressed in astrocytes and regulates BDNF-evoked calcium transients. Previous studies indicate that downregulation of TrkB-T1 in frontal cortex may be involved in neurobiological processes underlying suicide. Methods: In a microarray screening study (N=8), we interrogated all known microRNA in the frontal cortex of suicide completers with low expression of TrkB-T1 and normal controls. These findings were validated and followed up in a larger sample of cases and controls (N=55) Functional analyses included microRNA silencing, microRNA overexpression and luciferase assays to investigate specificity and to validate interactions between differentially expressed microRNA and TrkB-T1 Results: microRNAs Hsa-miR-185* and Hsa-miR-491-3p were upregulated in suicide completers with low expression of TrkB.T1 (Pnominal: 9.10-5 and 1.8.10-4 respectively; FDR-corrected p=0.031). Bioinformatic analyses revealed five putative binding sites for the DiGeorge syndrome linked microRNA Hsa-miR-185*in the 3M-bM-^@M-^YUTR of TrkB-T1, but none for Hsa-miR-491-3P. The increase of Hsa-miR-185* in frontal cortex of suicide completers was validated then confirmed in a larger, randomly selected group of suicide completers, where an inverse correlation between Hsa-miR-185* and TrkB-T1 expression was observed ( R=-0.404; p=0.002). Silencing and overexpression studies performed in human cell lines confirmed the inverse relationship between hsa-mir-185* and trkB-T1 expression. Luciferase assays demonstrated that Hsa-miR-185* binds to sequences in the 3M-bM-^@M-^YUTR of TrkB-T1. Conclusion: These results suggest that an increase of Hsa-miR-185* expression levels regulates, at least in part, the TrkB-T1 decrease observed in the frontal cortex of suicide completers and further implicate the 3MB 22q11 region in psychopathology. The microarray analysis consists in to compare the microRNA profile of four suicide completers with low TrkB-T1 expression level and four controls. Each RNA extract was labeled with Hy3 and hybridyzed with a reference sample labeled with Hy5. The reference sample was a pool of the eight RNA samples
2012-06-01 | E-GEOD-34120 | biostudies-arrayexpress
Project description:Suicide is the second leading cause of death globally among young people representing a significant global health burden. Although the molecular pathology of suicide remains poorly understood, it has been hypothesised that epigenomic processes may play a role. The objective of this study was to identify suicide-associated DNA methylation changes in the human brain by utilising previously published and unpublished methylomic datasets. We analyzed prefrontal cortex (PFC, n = 211) and cerebellum (CER, n = 114) DNA methylation profiles from suicide completers and non-psychiatric, sudden-death controls, meta-analyzing data from independent cohorts for each brain region separately. We report evidence for altered DNA methylation at several genetic loci in suicide cases compared to controls in both brain regions with suicide-associated differentially methylated positions enriched among functional pathways relevant to neuropsychiatric phenotypes and suicidality, including nervous system development (PFC) and regulation of long-term synaptic depression (CER). In addition, we examined the functional consequences of variable DNA methylation within a PFC suicide-associated differentially methylated region (PSORS1C3 DMR) using a dual luciferase assay and examined expression of nearby genes. DNA methylation within this region was associated with decreased expression of firefly luciferase but was not associated with expression of nearby genes, PSORS1C3 and POU5F1. Our data suggest that suicide is associated with DNA methylation, offering novel insights into the molecular pathology associated with suicidality. DNA from bulk post-mortem brain (human cerebellum) from 58 individuals
2020-02-27 | GSE137222 | GEO
Project description:Suicide is the second leading cause of death globally among young people representing a significant global health burden. Although the molecular pathology of suicide remains poorly understood, it has been hypothesised that epigenomic processes may play a role. The objective of this study was to identify suicide-associated DNA methylation changes in the human brain by utilising previously published and unpublished methylomic datasets. We analyzed prefrontal cortex (PFC, n = 211) and cerebellum (CER, n = 114) DNA methylation profiles from suicide completers and non-psychiatric, sudden-death controls, meta-analyzing data from independent cohorts for each brain region separately. We report evidence for altered DNA methylation at several genetic loci in suicide cases compared to controls in both brain regions with suicide-associated differentially methylated positions enriched among functional pathways relevant to neuropsychiatric phenotypes and suicidality, including nervous system development (PFC) and regulation of long-term synaptic depression (CER). In addition, we examined the functional consequences of variable DNA methylation within a PFC suicide-associated differentially methylated region (PSORS1C3 DMR) using a dual luciferase assay and examined expression of nearby genes. DNA methylation within this region was associated with decreased expression of firefly luciferase but was not associated with expression of nearby genes, PSORS1C3 and POU5F1. Our data suggest that suicide is associated with DNA methylation, offering novel insights into the molecular pathology associated with suicidality. DNA from bulk post-mortem brain (human cerebellum) from 33 individuals
2020-03-06 | GSE137223 | GEO