
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.23.609190
preprint
1
Article
Dynamic convergence of autism disorder risk genes across neurodevelopment
Fernandez Garcia Meilin http://orcid.org/0000-0002-8745-9775

Retallick-Townsley Kayla http://orcid.org/0000-0003-4706-5752

Pruitt April http://orcid.org/0000-0002-5807-5422

Davidson Elizabeth
Dai Yi
Fitzpatrick Sarah E. http://orcid.org/0000-0001-7446-6469

Sen Annabel
Cohen Sophie
Livoti Olivia
Khan Suha
Dossou Grace
Cheung Jen
Deans P.J. Michael
Wang Zuoheng
Huckins Laura http://orcid.org/0000-0002-5369-6502

Hoffman Ellen
Brennand Kristen http://orcid.org/0000-0003-0993-5956

24 8 2024
2024.08.23.609190https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.08.23.609190
nihpp-2024.08.23.609190.pdf
ABSTRACT

Over a hundred risk genes underlie risk for autism spectrum disorder (ASD) but the extent to which they converge on shared downstream targets to increase ASD risk is unknown. To test the hypothesis that cellular context impacts the nature of convergence, here we apply a pooled CRISPR approach to target 29 ASD loss-of-function genes in human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells, glutamatergic neurons, and GABAergic neurons. Two distinct approaches (gene-level and network-level analyses) demonstrate that convergence is greatest in mature glutamatergic neurons. Convergent effects are dynamic, varying in strength, composition, and biological role between cell types, increasing with functional similarity of the ASD genes examined, and driven by cell-type-specific gene co-expression patterns. Stratification of ASD genes yield targeted drug predictions capable of reversing gene-specific convergent signatures in human cells and ASD-related behaviors in zebrafish. Altogether, convergent networks downstream of ASD risk genes represent novel points of individualized therapeutic intervention.
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pmc
