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

TLDR

Most genetic risk for psychiatric disease lies in regulatory regions, implicating dysregulation of gene expression and splicing, yet comprehensive transcriptomic assessments of diseased brains remain limited. We integrated genotypes, RNA sequencing, and genomic data from 1,695 brain samples across ASD, schizophrenia, bipolar disorder, and controls to perform a transcriptome‑wide association study prioritizing cis‑mediated disease loci. Over a quarter of the transcriptome shows differential splicing or expression, with isoform‑level changes driving the strongest disease effects and genetic enrichments, while coexpression networks reveal disease‑specific neuronal and neural‑immune modules, offering a comprehensive resource for mechanistic insight and therapeutic development.

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.