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

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

Synaptic protein DLG2 controls neurogenic transcriptional programs disrupted in schizophrenia and related disorders

Genetic studies robustly implicate perturbation of DLG2-scaffolded mature postsynaptic signalling complexes in schizophrenia. Here we study in vitro cortical differentiation of DLG2-/- human embryonic stem cells via integrated phenotypic, gene expression and disease genetic analyses. This uncovers a developmental role for DLG2 in the regulation of neural stem cell proliferation and adhesion, and the activation of transcriptional programs during early excitatory corticoneurogenesis. Down-regulation of these programs in DLG2-/- lines delays expression of cell-type identity and causes marked deficits in neuronal migration, morphology and active properties. Genetic risk factors for neuropsychiatric and neurodevelopmental disorders converge on these neurogenic programs, each disorder displaying a distinct pattern of enrichment. These data unveil an intimate link between neurodevelopmental and mature signalling deficits contributing to disease - suggesting a dual role for known synaptic risk genes - and reveal a common pathophysiological framework for studying the neurodevelopmental origins of Mendelian and genetically complex mental disorders