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.

The predisposition to neuropsychiatric disease involves a complex, polygenic, and pleiotropic genetic architecture. However, little is known about how genetic variants impart brain dysfunction or pathology. We use transcriptomic profiling as a quantitative readout of molecular brain-based phenotypes across 5 major psychiatric disorders, including autism (ASD), schizophrenia (SCZ), bipolar disorder (BD), depression (MDD), and alcoholism (AAD), compared with matched controls. We identify patterns of shared and distinct gene-expression perturbations across these conditions. Notably, the degree of sharing of transcriptional dysregulation is related to polygenic (SNP-based) overlap across disorders, suggesting a significant causal genetic component. This comprehensive systems-level view of the neurobiological architecture of major neuropsychiatric illness demonstrates pathways of molecular convergence and specificity.

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Integration of sensory and molecular inputs from the environment shapes animal behavior. A major site of exposure to environmental molecules is the gastrointestinal tract, where dietary components are chemically transformed by the microbiota 1 and gut-derived metabolites are disseminated to all organs, including the brain 2 . In mice, the gut microbiota impacts behavior 3 , modulates neurotransmitter production in the gut and brain 4,5 , and influences brain development and myelination patterns 6,7 . Mechanisms mediating gut-brain interactions remain poorly defined, though broadly involve humoral or neuronal connections. We previously reported that levels of the microbial metabolite 4-ethylphenyl sulfate (4EPS) were elevated in a mouse model of atypical neurodevelopment 8 . Herein, we identified biosynthetic genes from the gut microbiome that mediate conversion of dietary tyrosine to 4-ethylphenol (4EP), and bioengineered gut bacteria to selectively produce 4EPS in mice. 4EPS entered the brain and was associated with changes in region-specific activity and functional connectivity. Gene expression signatures revealed altered oligodendrocyte function in the brain, and 4EPS impaired oligodendrocyte maturation in mice as well as decreased oligodendrocyte-neuron interactions in ex vivo brain cultures. Mice colonized with 4EP-producing bacteria exhibited reduced myelination of neuronal axons. Altered myelination dynamics in the brain have been associated with behavioral outcomes 7,[9][10][11][12][13][14]13,14 . Accordingly, we observed that mice exposed to 4EPS displayed anxiety-like behaviors, and pharmacologic treatments that promote oligodendrocyte differentiation prevented the behavioral effects of 4EPS. These findings reveal that a gut-derived molecule influences complex behaviors in mice via effects on oligodendrocyte function and myelin patterning in the brain.

Neuropsychiatric disorders classically lack defining brain pathologies, but recent work has demonstrated dysregulation at the molecular level, characterized by transcriptomic and epigenetic alterations1–3. In autism spectrum disorder (ASD), this molecular pathology involves the upregulation of microglial, astrocyte and neural–immune genes, the downregulation of synaptic genes, and attenuation of gene-expression gradients in cortex1,2,4–6. However, whether these changes are limited to cortical association regions or are more widespread remains unknown. To address this issue, we performed RNA-sequencing analysis of 725 brain samples spanning 11 cortical areas from 112 post-mortem samples from individuals with ASD and neurotypical controls. We find widespread transcriptomic changes across the cortex in ASD, exhibiting an anterior-to-posterior gradient, with the greatest differences in primary visual cortex, coincident with an attenuation of the typical transcriptomic differences between cortical regions. Single-nucleus RNA-sequencing and methylation profiling demonstrate that this robust molecular signature reflects changes in cell-type-specific gene expression, particularly affecting excitatory neurons and glia. Both rare and common ASD-associated genetic variation converge within a downregulated co-expression module involving synaptic signalling, and common variation alone is enriched within a module of upregulated protein chaperone genes. These results highlight widespread molecular changes across the cerebral cortex in ASD, extending beyond association cortex to broadly involve primary sensory regions.