3D genetic architecture of schizophrenia risk across three neuronal subtypes

Common genetic variants associated with schizophrenia risk are concentrated in non-coding regulatory sequences, but their precise target genes are context-dependent and impacted by cell-type-specific three-dimensional spatial chromatin organization. Here, we map long-range chromosomal conformations in human dopaminergic, GABAergic, and glutamatergic neurons to track developmentally programmed shifts in the regulatory activity of schizophrenia risk loci. Large-scale repressive compartmentalization, concomitant with the emergence of hundreds of neuron-specific multi-valent chromatin architectural stripes, occurs during neuronal differentiation, with genes interconnected to genetic risk loci through these long-range chromatin structures differing in their biological roles from genes more proximal to sequences conferring heritable risk. Functional targeting of chromatin loops involving the proximal risk gene SNAP91 and the distal putative risk gene BHLHE22 altered gene expression and neuronal phenotypes. Our findings highlight the large-scale cell-type-specific reorganization of chromosomal conformations at schizophrenia risk loci during neurodevelopment and provide functional validation of selected target genes implicated in the disorder through 3D chromatin looping.