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 disease brain are limited. Here, we integrate genotype and RNA-sequencing in brain samples from 1695 subjects with autism, schizophrenia, bipolar disorder and controls. Over 25% of the transcriptome exhibits differential splicing or expression, with isoform-level changes capturing the largest disease effects and genetic enrichments. co-expression networks isolate disease-specific neuronal alterations, as well as microglial, astrocyte, and interferon response modules defining novel neural-immune mechanisms. We prioritize disease loci likely mediated by cis-effects on brain expression via transcriptome-wide association analysis. This transcriptome-wide characterization of the molecular pathology across three major psychiatric disorders provides a comprehensive resource for mechanistic insight and therapeutic development.

Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain

“…Similarly, in human brain, genomic regions associated with schizophrenia are enriched for genes that show differential isoform usage across neurodevelopment 7 , implicating many schizophrenia-associated risk loci in the regulation of the expression of specific RNA transcripts. Consistent with these findings, examples of associations between psychiatric risk-associated loci and the abundance of novel, alternatively spliced transcripts are beginning to emerge [8][9][10] , complementing numerous reports of altered splicing patterns in the brains of psychiatric cases, compared to controls [11][12][13] .…”

Molecular Atlas of the Adult Mouse Brain

“…These spatial definitions have to a large extent been based on cytoarchitectural features -such as differences in the density and form of cells -as well as chemoarchitectural definitions derived from distribution of key molecules such as neurotransmitters (5,6). Ongoing collective efforts in the field are now starting to reveal the details of neuron and region connections at the microscale and mesoscale level (4,7,8), and gene expression in the human brain (9,10). These tissue definitions and the resulting mouse brain atlases (11,12) have been essential for establishing the experimental framework to explore brain structure and function relationships, but have also resulted in debate and disagreement over the validity of expert-based region annotations (13).…”

Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism

“…Finally, to evaluate whether the regulation networks related to ASD models could be conserved in human, we examined the expression levels of the hub genes with the data generated in an integrated transcriptional study using data sets of 2,000 high‐quality postmortem brain samples of individuals with SCZ or ASD [Gandal et al, ]. The significance of the alteration of expression levels of the hub genes based on student's t ‐test were calculated (Fig.…”

“…The results indicated that these hub genes were involved in drug abuse, bipolar disorder, depressive disorder, SCZ, and autistic disorder, which are a group of closely related disorders that may share some similar pathomechanisms with ASD. Finally, to evaluate whether the regulation networks related to ASD models could be conserved in human, we examined the expression levels of the hub genes with the data generated in an integrated transcriptional study using data sets of 2,000 high-quality postmortem brain samples of individuals with SCZ or ASD [Gandal et al, 2018]. The significance of the alteration of expression levels of the hub genes based on student's t-test were calculated (Fig.…”