Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD

Michael J. Gandal (), Jillian R. Haney, Brie Wamsley, Chloe X. Yap, Sepideh Parhami, Prashant S. Emani, Nathan Chang, George T. Chen, Gil D. Hoftman, Diego Alba, Gokul Ramaswami, Christopher L. Hartl, Arjun Bhattacharya, Chongyuan Luo, Ting Jin, Daifeng Wang, Riki Kawaguchi, Diana Quintero, Jing Ou, Ye Emily Wu, Neelroop N. Parikshak, Vivek Swarup, T. Grant Belgard, Mark Gerstein, Bogdan Pasaniuc and Daniel H. Geschwind ()
Additional contact information
Michael J. Gandal: University of California
Jillian R. Haney: University of California
Brie Wamsley: University of California
Chloe X. Yap: University of California
Sepideh Parhami: University of California
Prashant S. Emani: Yale University
Nathan Chang: Yale University
George T. Chen: University of California
Gil D. Hoftman: University of California
Diego Alba: University of California
Gokul Ramaswami: University of California
Christopher L. Hartl: University of California
Arjun Bhattacharya: University of California
Chongyuan Luo: University of California
Ting Jin: University of Wisconsin—Madison
Daifeng Wang: University of Wisconsin—Madison
Riki Kawaguchi: University of California
Diana Quintero: University of California
Jing Ou: University of California
Ye Emily Wu: University of California
Neelroop N. Parikshak: University of California
Vivek Swarup: University of California
T. Grant Belgard: The Bioinformatics CRO
Mark Gerstein: Yale University
Bogdan Pasaniuc: University of California
Daniel H. Geschwind: University of California

Nature, 2022, vol. 611, issue 7936, 532-539

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41586-022-05377-7

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