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Broad transcriptomic dysregulation across the cerebral cortex in ASD

Jillian R. Haney, Brie Wamsley, George T. Chen, Sepideh Parhami, Prashant S. Emani, Nathan Chang, Gil D. Hoftman, Diego de Alba, Gaurav Kale, Gokul Ramaswami, Christopher L. Hartl, Ting Jin, Daifeng Wang, Jing Ou, Ye Emily Wu, Neelroop N. Parikshak, Vivek Swarup, T. Grant Belgard, Mark Gerstein, Bogdan Pasaniuc, Michael J. Gandal, Daniel H. Geschwind
doi: https://doi.org/10.1101/2020.12.17.423129
Jillian R. Haney
1Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
2Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
3Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
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Brie Wamsley
1Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
2Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
3Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
4Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
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George T. Chen
2Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
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Sepideh Parhami
1Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
2Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
3Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
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Prashant S. Emani
8Computational Biology & Bioinformatics Program, Yale University, New Haven, CT 06520, USA
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Nathan Chang
8Computational Biology & Bioinformatics Program, Yale University, New Haven, CT 06520, USA
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Gil D. Hoftman
1Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
3Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
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Diego de Alba
3Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
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Gaurav Kale
3Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
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Gokul Ramaswami
1Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
2Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
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Christopher L. Hartl
1Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
2Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
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Ting Jin
9Waisman Center and Department of Biostatistics and Medical Informatics, University of Wisconsin – Madison, Madison, WI, 53705, USA
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Daifeng Wang
9Waisman Center and Department of Biostatistics and Medical Informatics, University of Wisconsin – Madison, Madison, WI, 53705, USA
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Jing Ou
2Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
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Ye Emily Wu
1Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
2Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
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Neelroop N. Parikshak
2Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
4Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
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Vivek Swarup
2Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
6Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697, USA
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T. Grant Belgard
10The Bioinformatics CRO, 203 Muirfield Cove West, Niceville, FL 32578, USA
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Mark Gerstein
8Computational Biology & Bioinformatics Program, Yale University, New Haven, CT 06520, USA
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Bogdan Pasaniuc
4Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
7Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, 90024, USA
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Michael J. Gandal
1Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
2Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
3Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
4Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
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  • For correspondence: mgandal@mednet.ucla.edu dhg@mednet.ucla.edu
Daniel H. Geschwind
1Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
2Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
3Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
4Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
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  • For correspondence: mgandal@mednet.ucla.edu dhg@mednet.ucla.edu
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Abstract

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 Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted December 18, 2020.
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Broad transcriptomic dysregulation across the cerebral cortex in ASD
Jillian R. Haney, Brie Wamsley, George T. Chen, Sepideh Parhami, Prashant S. Emani, Nathan Chang, Gil D. Hoftman, Diego de Alba, Gaurav Kale, Gokul Ramaswami, Christopher L. Hartl, Ting Jin, Daifeng Wang, Jing Ou, Ye Emily Wu, Neelroop N. Parikshak, Vivek Swarup, T. Grant Belgard, Mark Gerstein, Bogdan Pasaniuc, Michael J. Gandal, Daniel H. Geschwind
bioRxiv 2020.12.17.423129; doi: https://doi.org/10.1101/2020.12.17.423129
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Broad transcriptomic dysregulation across the cerebral cortex in ASD
Jillian R. Haney, Brie Wamsley, George T. Chen, Sepideh Parhami, Prashant S. Emani, Nathan Chang, Gil D. Hoftman, Diego de Alba, Gaurav Kale, Gokul Ramaswami, Christopher L. Hartl, Ting Jin, Daifeng Wang, Jing Ou, Ye Emily Wu, Neelroop N. Parikshak, Vivek Swarup, T. Grant Belgard, Mark Gerstein, Bogdan Pasaniuc, Michael J. Gandal, Daniel H. Geschwind
bioRxiv 2020.12.17.423129; doi: https://doi.org/10.1101/2020.12.17.423129

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