A CRISPR screen in human iPSC-derived neurons reveals convergent transcriptomic effects of neurodevelopmental disorder genes [CRISPR Screen]

Diverse risk genes have been identified for neurodevelopmental disorders (NDDs), but how these genes converge on similar biological pathways in neurons, and thus give rise to similar phenotypes, is unclear. Here, we apply a pooled CRISPR approach to target 23 (out of 29) NDD loss-of-function genes and examine convergent effects on gene expression across human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells, glutamatergic neurons, and GABAergic neurons. Points of convergence vary between these cell-types and are greatest in mature glutamatergic neurons, where they broadly regulate synaptic, epigenetic, and, unexpectedly, mitochondrial pathways. The strongest convergent networks were observed between NDD genes with shared biological annotations, clinical associations, and co-expression patterns in human post-mortem brain. Drugs that were predicted to reverse convergent transcriptomic signatures and/or arousal and sensory processing behaviors ameliorated behavioral phenotypes in NDD model zebrafish. These results suggest that convergent effects of NDD risk genes could provide clinically useful insights. Code and secondary analysis data can be found on Synapse ( ID=syn72039767, link=https://www.synapse.org/Synapse:syn72039767/wiki/636167)