PT  - JOURNAL ARTICLE
AU  - Jillian R. Haney
AU  - Brie Wamsley
AU  - George T. Chen
AU  - Sepideh Parhami
AU  - Prashant S. Emani
AU  - Nathan Chang
AU  - Gil D. Hoftman
AU  - Diego de Alba
AU  - Gaurav Kale
AU  - Gokul Ramaswami
AU  - Christopher L. Hartl
AU  - Ting Jin
AU  - Daifeng Wang
AU  - Jing Ou
AU  - Ye Emily Wu
AU  - Neelroop N. Parikshak
AU  - Vivek Swarup
AU  - T. Grant Belgard
AU  - Mark Gerstein
AU  - Bogdan Pasaniuc
AU  - Michael J. Gandal
AU  - Daniel H. Geschwind
TI  - Broad transcriptomic dysregulation across the cerebral cortex in ASD
AID  - 10.1101/2020.12.17.423129
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.12.17.423129
4099  - http://biorxiv.org/content/early/2020/12/18/2020.12.17.423129.short
4100  - http://biorxiv.org/content/early/2020/12/18/2020.12.17.423129.full
AB  - Classically, psychiatric disorders have been considered to lack defining pathology, but recent work has demonstrated consistent disruption at the molecular level, characterized by transcriptomic and epigenetic alterations.1–3 In ASD, upregulation of microglial, astrocyte, and immune signaling genes, downregulation of specific synaptic genes, and attenuation of regional gene expression differences are observed.1,2,4–6 However, whether these changes are limited to the cortical association areas profiled is unknown. Here, we perform RNA-sequencing (RNA-seq) on 725 brain samples spanning 11 distinct cortical areas in 112 ASD cases and neurotypical controls. We identify substantially more genes and isoforms that differentiate ASD from controls than previously observed. These alterations are pervasive and cortex-wide, but vary in magnitude across regions, roughly showing an anterior to posterior gradient, with the strongest signal in visual cortex, followed by parietal cortex and the temporal lobe. We find a notable enrichment of ASD genetic risk variants among cortex-wide downregulated synaptic plasticity genes and upregulated protein folding gene isoforms. Finally, using snRNA-seq, we determine that regional variation in the magnitude of transcriptomic dysregulation reflects changes in cellular proportion and cell-type-specific gene expression, particularly impacting L3/4 excitatory neurons. These results highlight widespread, genetically-driven neuronal dysfunction as a major component of ASD pathology in the cerebral cortex, extending beyond association cortices to involve primary sensory regions.Competing Interest StatementThe authors have declared no competing interest.