Sanders, B, D’Andrea, D, Collins, MO, Rees, E, Steward, TGJ, Zhu, Y, Chapman, G, Legge, SE, Pardiñas, AF, Harwood, AJ, Gray, WP, O’Donovan, MC, Owen, MJ, Errington, AC, Blake, DJ, Whitcomb, DJ, Pocklington, AJ and Shin, E ORCID: https://orcid.org/0000-0002-8865-6834 (2021) DLG2 knockout reveals neurogenic transcriptional programs underlying neuropsychiatric disorders and cognition. medRxiv.

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Abstract

<jats:title>Abstract</jats:title><jats:p>Brain development requires a complex choreography of cell proliferation, specialisation, migration and network formation, guided by the activation and repression of gene expression programs. It remains unclear how this process is disrupted in neuropsychiatric disorders. Here we integrate human genetics with transcriptomic data from the differentiation of human embryonic stem cells into cortical excitatory neurons. This reveals a cascade of transcriptional programs, activated during early corticoneurogenesis <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic>, in which genetic variation is robustly associated with neuropsychiatric disorders and cognitive function. Within these early neurogenic programs, genetic risk is concentrated in loss-of-function intolerant (LoFi) genes, capturing virtually all LoFi disease association. Down-regulation of these programs in <jats:italic>DLG2</jats:italic> knockout lines delays expression of cell-type identity alongside marked deficits in neuronal migration, morphology and action potential generation, validating computational predictions. These data implicate specific cellular pathways and neurodevelopmental processes in the aetiology of multiple neuropsychiatric disorders and cognition.</jats:p>

Item Type: Article
Additional Information: This article has not been currently accepted or published in a peer reviewed journal. It's been published via medRxiv. For any copyright requirements, please go to their website at; https://www.biorxiv.org/content/10.1101/2020.01.10.898676v2 Any acceptance dates, or publication details will be updated when required.
Subjects: R Medicine > R Medicine (General) > R735 Medical education. Medical schools. Research
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Divisions: Faculty of Natural Sciences > School of Life Sciences
Depositing User: Symplectic
Date Deposited: 26 Jan 2022 14:18
Last Modified: 26 Jan 2022 14:18
URI: https://eprints.keele.ac.uk/id/eprint/10530

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