DLG2 knockout reveals early neurodevelopmental transcriptional programs disrupted in schizophrenia and a wide spectrum of related disorders

Harmonised processes of cell proliferation, neuronal birth, growth, migration and wiring underlie brain development. Yet, which of these processes are disrupted in schizophrenia (SZ) is to be unveiled. We demonstrate that DLG2, found in de novo single gene CNV of SZ, has a distinct neurodevelopmental role during corticoneurogenesis controlling proliferation of neural precursors and guiding new-born neurons through migration and maturation. SZ common risk variants were significantly enriched in two specific transcriptional programs that are normally switched on and active during corticoneurogenesis but down-regulated in DLG2-/- neurons. In addition, these transcriptional programs display enrichment for both rare and common risk variants for severe neurodevelopmental delay, autism spectrum disorder, ADHD, SZ and bipolar disorder in a unique profile, supporting the neurodevelopmental continuum/gradient model. The current study pinpoints disease-relevant specific transcriptional programs underlying corticoneurogenesis, sketching a coherent pathophysiological framework and providing the future neurodevelopmental research direction.