Dynamic neuro-immune regulation of psychiatric risk loci in human neurons.

The immune environment influences neurodevelopment and subsequent clinical trajectories for psychiatric outcomes in childhood and adolescence. Yet it remains unclear if the impact of maternal and fetal immune activation varies with distinct polygenic risk profiles. Therefore, here we catalog genotype and environment (GxE) interactions, contrasting allele-specific regulatory activity between inflammatory cues. We report a cue-specific neuronal massively parallel reporter assay (MPRA) of 152 loci from genome-wide association studies (GWAS) of ten brain traits/disorders, empirically dissecting the impact of interleukin-6 (IL-6) and interferon-alpha (IFNα) on transcriptional activity. In human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons, 1,156 active candidate regulatory risk sequences (MPRA-active CRSs) are resolved, including 267 with variant-specific effects (MPRA-emVars) and 61 with variant-by-cytokine interaction effects (interaction MPRA-emVars). Broadly, neuronal immune-mediated regulatory activity is associated with differences in transcription factor binding and chromatin accessibility, the gene targets of which show pleiotropic enrichments for brain, metabolic, and immune disorders. Dynamic genetic regulation mediates neuroimmune effects, informing our understanding of the genomics of psychiatric and neurological traits, mechanisms governing pleiotropy across disorders, and how immune mechanisms mediate genetic risk.