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

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 () and Eunju Shin ()
Additional contact information
Bret Sanders: Neuroscience and Mental Health Research Institute, Cardiff University
Daniel D’Andrea: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University
Mark O. Collins: University of Sheffield
Elliott Rees: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University
Tom G. J. Steward: University of Bristol
Ying Zhu: Neuroscience and Mental Health Research Institute, Cardiff University
Gareth Chapman: Neuroscience and Mental Health Research Institute, Cardiff University
Sophie E. Legge: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University
Antonio F. Pardiñas: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University
Adrian J. Harwood: Neuroscience and Mental Health Research Institute, Cardiff University
William P. Gray: Neuroscience and Mental Health Research Institute, Cardiff University
Michael C. O’Donovan: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University
Michael J. Owen: Neuroscience and Mental Health Research Institute, Cardiff University
Adam C. Errington: Neuroscience and Mental Health Research Institute, Cardiff University
Derek J. Blake: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University
Daniel J. Whitcomb: University of Bristol
Andrew J. Pocklington: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University
Eunju Shin: Neuroscience and Mental Health Research Institute, Cardiff University

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-021-27601-0

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