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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; Steward, Tom G.J.; Zhu, Ying; Chapman, Gareth; Legge, Sophie E.; Pardiñas, Antonio F.; Harwood, Adrian J.; Gray, William P.; O’Donovan, Michael C.; Owen, Michael J.; Errington, Adam C.; Blake, Derek J.; Whitcomb, Daniel J.; Pocklington, Andrew J.; Shin, Eunju

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


Authors

Bret Sanders

Daniel D’Andrea

Mark O. Collins

Elliott Rees

Tom G.J. Steward

Ying Zhu

Gareth Chapman

Sophie E. Legge

Antonio F. Pardiñas

Adrian J. Harwood

William P. Gray

Michael C. O’Donovan

Michael J. Owen

Adam C. Errington

Derek J. Blake

Daniel J. Whitcomb

Andrew J. Pocklington



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.

Journal Article Type Article
Acceptance Date Dec 1, 2021
Publication Date Jan 14, 2022
Publicly Available Date May 30, 2023
Journal Nature Communications
Print ISSN 2041-1723
Peer Reviewed Peer Reviewed
Volume 13
Article Number 27
DOI https://doi.org/10.1038/s41467-021-27601-0
Publisher URL https://www.nature.com/articles/s41467-021-27601-0

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