Orphan GPCRs as Targets for Human Brain Modulation: A Multi-omic Atlas of Cell-Type Specific Expression

G Protein coupled receptors (GPCRs) are the largest class of clinically validated drug targets with nearly 35% of all approved therapeutic agents acting on these receptors. To further explore the potential of this class of receptors for the development of circuit-specific and mechanism-based therapeutic strategies for neurological disorders, we focused on GPCRs with no known endogenous ligand, orphan GPCRs (oGPCRs), because knowledge of their functions in the human brain remains rudimentary. Here, we utilized fluorescence activated nuclear sorting and sequencing (FANSseq) to generate deep molecular profiles of cell type specific nuclei isolated from post-mortem brains to generate an atlas of oGPCR expression across multiple regions of the human brain. We identified 22 oGPCRs that displayed selective cell-type enrichment both in RNA transcript expression and chromatin accessibility. We further validated each of these targets for cell-type specific expression in human brains and developed an open-source web atlas of all oGPCR expression in the human brain to serve as a neuro-resource for the broader scientific community. These studies reveal novel cell-type specific expression patterns of several oGPCRs, suggest potential endogenous roles for these receptors, and identify validated candidates for cell-type specific neuromodulation of the human brain. One Sentence Summary This study presents an atlas of orphan GPCR expression across the human brain for translational targeting.