Neuropsychiatric disorders classically lack defining brain pathologies, but recent work has demonstrated dysregulation at the molecular level, characterized by transcriptomic and epigenetic alterations. In autism spectrum disorder (ASD), this molecular pathology involves up-regulation of microglial, astrocyte and neuroimmune genes, down-regulation of synaptic genes and attenuation of gene expression gradients in the cortex. However, whether these changes are limited to cortical association regions or are more widespread remains unknown. To address this problem, Michael J. Gandal and colleagues from several American institutions (Lifespan Brain Institute at Penn Medicine and The Children’s Hospital of PhiladelphiaDepartment of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA; Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Center for Autism Research and Treatment, Semel Institute of Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA_; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California,_ Los Angeles, CA, USA; Department of Human Genetics, David Geffen School of Medicine, University of California,

Los Angeles, CA, USA) performed RNA sequencing analysis of 725 brain samples spanning 11 cortical areas from 112 post-mortem samples from individuals with ASD and neurotypical controls. They found widespread transcriptomic changes in the cortex in ASD, exhibiting an anterior to posterior gradient, with the largest differences in the primary visual cortex, coinciding with an attenuation of typical transcriptomic differences between cortical regions. Single nucleotide RNA sequencing and methylation profiling demonstrate that this robust molecular signature reflects cell type-specific gene expression changes, particularly affecting excitatory neurons and glia. Both rare and common gene variation associated with ASD converge within a down-regulated coexpression module involving synaptic signaling, and common variation alone is enriched within an up-regulated protein chaperone gene module. These results highlight widespread molecular changes in the cerebral cortex in ASD that extend beyond the association cortex to broadly involve primary sensory regions.

Transcriptomic differences associated with Autism in 11 cortical regions.
Transcriptomic regional identity attenuation throughout the cortex in ASD.
Coexpression network analysis characterizes the dysregulation of ASD risk genes throughout the cortex.
Functional characterization of regionally variable transcriptomic dysregulation in ASD.

Gandal, M.J., Haney, J.R., Wamsley, B. et al. Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD. Nature (2022). s41586-022-05377-7.



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