Dynamic convergence of autism disorder risk genes across neurodevelopment.

Over a hundred risk genes underlie risk for autism spectrum disorder (ASD) but the extent to which they converge on shared downstream targets to increase ASD risk is unknown. To test the hypothesis that cellular context impacts the nature of convergence, here we apply a pooled CRISPR approach to target 29 ASD loss-of-function genes in human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells, glutamatergic neurons, and GABAergic neurons. Two distinct approaches (gene-level and network-level analyses) demonstrate that convergence is greatest in mature glutamatergic neurons.

Dynamic stress- and inflammatory-based regulation of psychiatric risk loci in human neurons.

The prenatal environment can alter neurodevelopmental and clinical trajectories, markedly increasing risk for psychiatric disorders in childhood and adolescence. To understand if and how fetal exposures to stress and inflammation exacerbate manifestation of genetic risk for complex brain disorders, we report a large-scale context-dependent massively parallel reporter assay (MPRA) in human neurons designed to catalogue genotype x environment (GxE) interactions. Across 240 genome-wide association study (GWAS) loci linked to ten brain traits/disorders, the impact of hydrocortisone, interleukin 6, and interferon alpha on transcriptional activity is empirically evaluated in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons.