Etiological basis for chronic pain genetic variation in brain and dorsal root ganglia cell types

Chronic pain is a complex clinical problem comprising multiple conditions that may share a common genetic profile. Genome-wide association studies (GWAS) have identified many risk loci whose cell-type context remains unclear. Here, we integrated GWAS data on chronic pain (N = 1,235,695) with single-cell RNA sequencing (scRNA-seq) data from human brain and dorsal root ganglia (hDRG), and single-cell chromatin accessibility data from human brain and mouse dorsal horn. Pain-associated variants were enriched in glutamatergic neurons; mainly in prefrontal cortex, hippocampal CA1-3, and amygdala. In hDRG, the hPEP.TRPV1/A1.2 neuronal subtype showed robust enrichment. Chromatin accessibility analyses revealed variant enrichment in excitatory and inhibitory neocortical neurons in brain and in midventral neurons and oligodendrocyte precursor cells in the mouse dorsal horn. Gene-level heritability in the brain highlighted roles for kinase activity, GABAergic synapses, axon guidance, and neuron projection development. In hDRG, implicated genes related to glutamatergic signaling and neuronal projection. In cervical DRG of patients with acute or chronic pain (N = 12), scRNA-seq data from neuronal or non-neuronal cells were enriched for chronic pain-associated genes (e.g., EFNB2, GABBR1, NCAM1, SCN11A). This cell-type-specific genetic architecture of chronic pain across central and peripheral nervous system circuits provides a foundation for targeted translational research.