Dataset Information

Integrative Transcriptomics Reveals Sexually Dimorphic Control of the Cholinergic/Neurokine Interface in Schizophrenia and Bipolar Disorder.

ABSTRACT: RNA sequencing analyses are often limited to identifying lowest p value transcripts, which does not address polygenic phenomena. To overcome this limitation, we developed an integrative approach that combines large-scale transcriptomic meta-analysis of patient brain tissues with single-cell sequencing data of CNS neurons, short RNA sequencing of human male- and female-originating cell lines, and connectomics of transcription factor and microRNA interactions with perturbed transcripts. We used this pipeline to analyze cortical transcripts of schizophrenia and bipolar disorder patients. Although these pathologies show massive transcriptional parallels, their clinically well-known sexual dimorphisms remain unexplained. Our method reveals the differences between afflicted men and women and identifies disease-affected pathways of cholinergic transmission and gp130-family neurokine controllers of immune function interlinked by microRNAs. This approach may open additional perspectives for seeking biomarkers and therapeutic targets in other transmitter systems and diseases.

SUBMITTER: Lobentanzer S

PROVIDER: S-EPMC6899527 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Integrative Transcriptomics Reveals Sexually Dimorphic Control of the Cholinergic/Neurokine Interface in Schizophrenia and Bipolar Disorder.

Lobentanzer Sebastian S Hanin Geula G Klein Jochen J Soreq Hermona H

Cell reports 20191001 3

RNA sequencing analyses are often limited to identifying lowest p value transcripts, which does not address polygenic phenomena. To overcome this limitation, we developed an integrative approach that combines large-scale transcriptomic meta-analysis of patient brain tissues with single-cell sequencing data of CNS neurons, short RNA sequencing of human male- and female-originating cell lines, and connectomics of transcription factor and microRNA interactions with perturbed transcripts. We used th ...[more]

PMID: 31618642

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Project description:Background Neuropsychiatric disorders such as Schizophrenia (SCZ) and Bipolar disorder (BPD) pose a broad range of problems with different symptoms mainly characterized by some combination of abnormal thoughts, emotions, behaviour, etc. However, in depth molecular and pathophysiological mechanisms among different neuropsychiatric disorders have not been clearly understood yet. We have used RNA-seq data to investigate unique and overlapping molecular signatures between SCZ and BPD using an integrative network biology approach. Methods RNA-seq count data were collected from NCBI-GEO database generated on post-mortem brain tissues of controls (n = 24) and patients of BPD (n = 24) and SCZ (n = 24). Differentially expressed genes (DEGs) were identified using the consensus of DESeq2 and edgeR tools and used for downstream analysis. Weighted gene correlation networks were constructed to find non-preserved (NP) modules for SCZ, BPD and control conditions. Topological analysis and functional enrichment analysis were performed on NP modules to identify unique and overlapping expression signatures during SCZ and BPD conditions. Results We have identified four NP modules from the DEGs of BPD and SCZ. Eleven overlapping genes have been identified between SCZ and BPD networks, and they were found to be highly enriched in inflammatory responses. Among these eleven genes, TNIP2, TNFRSF1A and AC005840.1 had higher sum of connectivity exclusively in BPD network. In addition, we observed that top five genes of NP module from SCZ network were downregulated which may be a key factor for SCZ disorder. Conclusions Differential activation of the immune system components and pathways may drive the common and unique pathogenesis of the BPD and SCZ. Highlights • Common and unique molecular signatures were identified between BPD and SCZ using integrative network biology approach.• Non-preserved (NP) modules for SCZ, BPD and control conditions are found to be associated with the differential regulation of neuroinflammatory process.• Overlapping and disease-specific genes and pathways may provide therapeutic intervention or prevention of BPD and SCZ.

Dataset Information

Integrative Transcriptomics Reveals Sexually Dimorphic Control of the Cholinergic/Neurokine Interface in Schizophrenia and Bipolar Disorder.

Publications

Integrative Transcriptomics Reveals Sexually Dimorphic Control of the Cholinergic/Neurokine Interface in Schizophrenia and Bipolar Disorder.

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