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

• Published in: Nature communications Vol. 13; no. 1; p. 27
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.01.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/100; 13/106; 14; 14/1; 14/19; 38; 38/91; 42/41; 631/136/368/2430; 631/337/2019; 631/378/1689/1799; 631/532/1360; 82/58; 9/74; Action potential; Animals; Brain; Cell Differentiation; Cerebral Cortex - cytology; Cerebral Cortex - embryology; Cerebral Cortex - metabolism; Cognition; Cognitive ability; Convergence; Differentiation; Disorders; Embryo cells; Embryogenesis; Female; Gene expression; Gene Expression Regulation, Developmental; Gene Knockdown Techniques; Genetic analysis; Genetic diversity; Genetic Predisposition to Disease; Genetic variance; Genetics; Guanylate Kinases - genetics; Guanylate Kinases - metabolism; Human Embryonic Stem Cells - metabolism; Humanities and Social Sciences; Humans; Maturation; Mental disorders; Mental Disorders - genetics; multidisciplinary; Neurogenesis; Neurogenesis - genetics; Neurogenesis - physiology; Neurons; Pregnancy; Schizophrenia; Schizophrenia - genetics; Science; Science (multidisciplinary); Statistical analysis; Stem cells; Transcription; Transcriptome; Transcriptomics; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27601-0

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. Coordinated programs of gene expression drive brain development. Here, the authors use human embryonic stem cells and foetal cortical tissue as well as available GWAS statistics and analysis of genetic variants associated with neuropsychiatric disorders and cognition revealing a convergence on transcriptional programs regulating excitatory cortical neurogenesis.