Transcriptional programs regulating neuronal differentiation are disrupted in DLG2 knockout human embryonic stem cells and enriched for schizophrenia and related disorders risk variants

Sanders, Bret, D'Andrea, Daniel, Collins, Mark O., Rees, Elliott ORCID: https://orcid.org/0000-0002-6168-9222, Steward, Tom G. J., Zhu, Ying, Chapman, Gareth, Legge, Sophie E., Pardinas, Antonio F. ORCID: https://orcid.org/0000-0001-6845-7590, Harwood, Adrian J. ORCID: https://orcid.org/0000-0003-3124-5169, Gray, William P. ORCID: https://orcid.org/0000-0001-7595-8887, O'Donovan, Michael C. ORCID: https://orcid.org/0000-0001-7073-2379, Owen, Michael J. ORCID: https://orcid.org/0000-0003-4798-0862, Errington, Adam C. ORCID: https://orcid.org/0000-0002-2171-389X, Blake, Derek J. ORCID: https://orcid.org/0000-0002-5005-4731, Whitcomb, Daniel J., Pocklington, Andrew J. ORCID: https://orcid.org/0000-0002-2137-0452 and Shin, Eunju ORCID: https://orcid.org/0000-0002-8865-6834 2022. Transcriptional programs regulating neuronal differentiation are disrupted in DLG2 knockout human embryonic stem cells and enriched for schizophrenia and related disorders risk variants. Nature Communications 13 (1) , 27. 10.1038/s41467-021-27601-0

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Abstract

Coordinated programs of gene expression drive brain development. It is unclear which transcriptional programs, in which cell-types, are affected in neuropsychiatric disorders such as schizophrenia. Here we integrate human genetics with transcriptomic data from differentiation of human embryonic stem cells into cortical excitatory neurons. We identify transcriptional programs expressed during early neurogenesis in vitro and in human foetal cortex that are down-regulated in DLG2−/− lines. Down-regulation impacted neuronal differentiation and maturation, impairing migration, morphology and action potential generation. Genetic variation in these programs is associated with neuropsychiatric disorders and cognitive function, with associated variants predominantly concentrated in loss-of-function intolerant genes. Neurogenic programs also overlap schizophrenia GWAS enrichment previously identified in mature excitatory neurons, suggesting that pathways active during prenatal cortical development may also be associated with mature neuronal dysfunction. Our data from human embryonic stem cells, when combined with analysis of available foetal cortical gene expression data, de novo rare variants and GWAS statistics for neuropsychiatric disorders and cognition, reveal a convergence on transcriptional programs regulating excitatory cortical neurogenesis.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) Biosciences MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine Neuroscience and Mental Health Research Institute (NMHRI)
Additional Information:	This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher:	Nature Research
ISSN:	2041-1723
Funders:	MRC, Wellcome Trust
Date of First Compliant Deposit:	24 January 2022
Date of Acceptance:	1 December 2021
Last Modified:	14 Sep 2024 01:30
URI:	https://orca.cardiff.ac.uk/id/eprint/146865

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