Journal Article

Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD

Pasaniuc, Bogdan, Geschwind, Daniel H., Chang, Nathan, Bhattacharya, Arjun, Quintero, Diana, Yap, Chloe X., Hoftman, Gil D., Emani, Prashant S., Ramaswami, Gokul, Wang, Daifeng, Gandal, Michael J., de Alba, Diego, Haney, Jillian R., Jin, Ting, Kawaguchi, Riki, Ou, Jing, Wamsley, Brie, Wu, Ye Emily, Chen, George T., Gerstein, Mark, Hartl, Christopher L., Swarup, Vivek, Parikshak, Neelroop N., Parhami, Sepideh, Belgard, T. Grant, Luo, Chongyuan

2022

Overview

Neuropsychiatric disorders classically lack defining brain pathologies, but recent work has demonstrated dysregulation at the molecular level, characterized by transcriptomic and epigenetic alterations 1 – 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 cortex 1 , 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. RNA sequencing reveals widespread transcriptomic changes across the cerebral cortex in autism spectrum disorder, including primary sensory regions, in addition to association regions, as well as an attenuation of regional identity.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38 / 38/39 / 45 / 45/91 / 631/114/2114 / 631/208/212/2019 / 631/208/514/1949 / 631/378/2583 / 692/699/476/1373 / Attenuation / Autism / Autism Spectrum Disorder - genetics / Autism Spectrum Disorder - metabolism / Autism Spectrum Disorder - pathology / Autopsy / Brain / Cerebral cortex / Cerebral Cortex - metabolism / Cerebral Cortex - pathology / Epigenetics / Gene expression / Gene sequencing / Genes / Genetic diversity / Genetic Variation / Humanities and Social Sciences / Humans / Mental disorders / Modules / multidisciplinary / Neuroglia - metabolism / Neuronal-glial interactions / Neurons - metabolism / Pathology / Primary Visual Cortex - metabolism / Ribonucleic acid / RNA / RNA - analysis / RNA - genetics / Science / Science (multidisciplinary) / Sequence analysis / Sequence Analysis, RNA / Somatosensory cortex / Synaptic transmission / Transcriptome - genetics / Transcriptomics / Visual cortex