Dataset Information

Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder.

ABSTRACT: Most genetic risk for psychiatric disease lies in regulatory regions, implicating pathogenic dysregulation of gene expression and splicing. However, comprehensive assessments of transcriptomic organization in diseased brains are limited. In this work, we integrated genotypes and RNA sequencing in brain samples from 1695 individuals with autism spectrum disorder (ASD), schizophrenia, and bipolar disorder, as well as controls. More than 25% of the transcriptome exhibits differential splicing or expression, with isoform-level changes capturing the largest disease effects and genetic enrichments. Coexpression networks isolate disease-specific neuronal alterations, as well as microglial, astrocyte, and interferon-response modules defining previously unidentified neural-immune mechanisms. We integrated genetic and genomic data to perform a transcriptome-wide association study, prioritizing disease loci likely mediated by cis effects on brain expression. This transcriptome-wide characterization of the molecular pathology across three major psychiatric disorders provides a comprehensive resource for mechanistic insight and therapeutic development.

SUBMITTER: Gandal MJ

PROVIDER: S-EPMC6443102 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder.

Gandal Michael J MJ Zhang Pan P Hadjimichael Evi E Walker Rebecca L RL Chen Chao C Liu Shuang S Won Hyejung H van Bakel Harm H Varghese Merina M Wang Yongjun Y Shieh Annie W AW Haney Jillian J Parhami Sepideh S Belmont Judson J Kim Minsoo M Moran Losada Patricia P Khan Zenab Z Mleczko Justyna J Xia Yan Y Dai Rujia R Wang Daifeng D Yang Yucheng T YT Xu Min M Fish Kenneth K Hof Patrick R PR Warrell Jonathan J Fitzgerald Dominic D White Kevin K Jaffe Andrew E AE Peters Mette A MA Gerstein Mark M Liu Chunyu C Iakoucheva Lilia M LM Pinto Dalila D Geschwind Daniel H DH

Science (New York, N.Y.) 20181201 6420

Most genetic risk for psychiatric disease lies in regulatory regions, implicating pathogenic dysregulation of gene expression and splicing. However, comprehensive assessments of transcriptomic organization in diseased brains are limited. In this work, we integrated genotypes and RNA sequencing in brain samples from 1695 individuals with autism spectrum disorder (ASD), schizophrenia, and bipolar disorder, as well as controls. More than 25% of the transcriptome exhibits differential splicing or ex ...[more]

PMID: 30545856

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Project description:Schizophrenia (SCZ) and bipolar disorder (BPD) are severe mental disorders with high heritability. Clinicians have long noticed the similarities of clinic symptoms between these disorders. In recent years, accumulating evidence indicates some shared genetic liabilities. However, what is shared remains elusive. In this study, we conducted whole transcriptome analysis of post-mortem brain tissues (cingulate cortex) from SCZ, BPD and control subjects, and identified differentially expressed genes in these disorders. We found 105 and 153 genes differentially expressed in SCZ and BPD, respectively. By comparing the t-test scores, we found that many of the genes differentially expressed in SCZ and BPD are concordant in their expression level (q?0.01, 53 genes; q?0.05, 213 genes; q?0.1, 885 genes). Using genome-wide association data from the Psychiatric Genomics Consortium, we found that these differentially and concordantly expressed genes were enriched in association signals for both SCZ (P<10(-7)) and BPD (P=0.029). To our knowledge, this is the first time that a substantially large number of genes show concordant expression and association for both SCZ and BPD. Pathway analyses of these genes indicated that they are involved in the lysosome, Fc gamma receptor-mediated phagocytosis, regulation of actin cytoskeleton pathways, along with several cancer pathways. Functional analyses of these genes revealed an interconnected pathway network centered on lysosomal function and the regulation of actin cytoskeleton. These pathways and their interacting network were principally confirmed by an independent transcriptome sequencing data set of the hippocampus. Dysregulation of lysosomal function and cytoskeleton remodeling has direct impacts on endocytosis, phagocytosis, exocytosis, vesicle trafficking, neuronal maturation and migration, neurite outgrowth and synaptic density and plasticity, and different aspects of these processes have been implicated in SCZ and BPD.

Dataset Information

Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder.

Publications

Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder.

Similar Datasets

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