Mapping cis-Regulatory Chromatin Contacts in Neural Cells Links Neuropsychiatric Disorder Risk Variants to Target Genes

Mutations in gene regulatory elements have been associated with a wide range of complex neuropsychiatric disorders. However, due to their cell-type specificity and difficulties in characterizing their regulatory targets, the ability to identify causal genetic variants has remained limited. To address these constraints, we perform integrative analysis of chromatin interactions using promoter capture Hi-C (pcHi-C), open chromatin regions using ATAC-seq, and transcriptomes using RNA-seq in four functionally distinct neural cell types: iPSC-induced excitatory neurons and lower motor neurons, iPSC-derived hippocampal dentate gyrus (DG)-like neurons, and primary astrocytes. We identify hundreds of thousands of long-range cis interactions between promoters and distal promoter-interacting regions (PIRs), enabling us to link regulatory elements to their target genes and reveal putative processes that are dysregulated in disease. Finally, we validate several PIRs using CRISPR techniques in human excitatory neurons, demonstrating that CDK5RAP3, STRAP, and DRD2 are transcriptionally regulated by physically linked enhancers.