Exome-wide association study reveals common and rare coding variants shaping chronic pain in 327,642 UK biobank participants.

backgroundChronic pain is a major global health burden with a substantial but incompletely understood genetic basis. Although genome-wide association studies have identified multiple common-variant loci for pain-related traits, the contribution of rare coding variants to chronic pain susceptibility, biological mechanisms, and shared architecture across pain phenotypes remains unclear.

methodsWe performed an exome-wide association study across ten chronic pain phenotypes using whole-exome sequencing data from 327,642 European participants in the UK Biobank. Variant-level and gene-level association analyses were conducted to identify common and rare coding signals. Downstream analyses included conditional analysis, statistical fine-mapping, validation in non-European populations, replication in independent cohorts, cross-trait meta-analysis, colocalization, pathway and tissue enrichment, single-cell enrichment, summary-data-based Mendelian randomization, and estimation of heritability and genetic correlation from common and rare variants.

resultsWe identified 286 significant variant-level associations arising from 235 unique variants mapped to 117 genes, including 13 novel lead variants and 44 independent lead signals. Gene-level analyses identified ten significant genes driven predominantly by rare functional variants: ADAMTSL5, ANKRD12, ARID5A, DPP7, GMCL1, HCK, KIF20B, SLC13A1, UBR2, and ZNF558. Functional analyses implicated pathways related to nervous system development, axonogenesis, and synaptic organization, with enrichment in brain tissues and hTRPM8-expressing dorsal root ganglion neurons. Mendelian randomization analyses highlighted convergent regulatory effects across neural and immune-related tissues. Heritability analyses showed that rare coding variants explained a modest proportion of variance relative to common variants but exhibited larger average effects in the most damaging functional classes, particularly high-confidence loss-of-function variants. Genetic correlation analyses revealed shared genetic components among chronic pain conditions and positive correlations with selected psychiatric and nervous system disorders.

conclusionsThese findings provide a comprehensive map of coding variation underlying chronic pain and show that both common and rare coding variants contribute to its genetic architecture. Rare coding variants explain only a limited fraction of heritability but offer strong mechanistic insight by implicating discrete genes and pathways related to neuronal development, neuroimmune signaling, and tissue homeostasis. This work advances understanding of chronic pain biology and provides a foundation for future multi-ancestry studies and functional validation.