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.