Patterns of Shared and Distinct Transcriptomic Dysregulation across Psychiatric Disorders

Background: Our understanding of the pathophysiology of neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia (SCZ), and bipolar disorder (BD), lags behind other fields of medicine. Defining genetic contributions to disease risk provides a rigorous foothold for biological, mechanistic understanding but is challenged by genetic complexity, polygenicity, and substantial pleiotropy, in which genetic variants are associated with multiple distinct phenotypes.

Objectives: We reasoned that transcriptome profiling can provide a quantitative biological context for interpreting the molecular effects of disease-associated genetic variants and for identifying shared and distinct molecular pathways disrupted across major neuropsychiatric disorders.

Methods: We integrated SNP-genotypes with RNA sequencing in brain samples from 1695 individuals with ASD, SCZ, and BD, as well as controls. We performed comprehensive analysis across multiple levels of transcriptomic organization, including gene and transcript-isoform expression and coexpression networks for both protein-coding and noncoding genes.

Results: 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. A distinct upregulation of microglial-associated genes clearly differentiates ASD from the other disorders, providing biological insights into disease specificity.

Conclusions: This large-scale integration of genetic and genomic data in human brain enables a comprehensive systems-level view of the neurobiological architecture of major neuropsychiatric illness, demonstrating pathways of molecular convergence and specificity, and provides a resource for mechanistic insight and therapeutic development.