CHRONIC pain is influenced by both common and rare genetic variants, with newly identified associations highlighting potential biological mechanisms underlying pain susceptibility, according to an exome wide association study of 327,642 participants. The findings identify genetic signals linked to ten chronic pain phenotypes and provide further insight into the neuronal and immune related pathways that may contribute to chronic pain.
Researchers analysed whole exome sequencing data from 327,642 participants of European ancestry in the UK Biobank, examining ten chronic pain phenotypes. The study investigated how common and rare coding variants contributed to chronic pain susceptibility, including their potential biological effects and shared genetic architecture across pain conditions.
Variant level analyses identified 286 significant associations involving 235 unique variants mapped to 117 genes. These included 13 novel lead variants and 44 independent lead signals. At the gene level, analyses identified ten significant genes driven predominantly by rare functional variants: ADAMTSL5, ANKRD12, ARID5A, DPP7, GMCL1, HCK, KIF20B, SLC13A1, UBR2 and ZNF558.
These results expand the catalogue of genetic associations with chronic pain and indicate that multiple forms of coding variation contribute to its underlying biology.
Functional analyses implicated pathways involved in nervous system development, axon formation and synaptic organisation. Researchers also identified enrichment in brain tissues and dorsal root ganglion neurons expressing hTRPM8, a receptor associated with sensory signalling.
Mendelian randomisation analyses highlighted convergent regulatory effects across neural and immune related tissues, suggesting potential connections between nervous system activity and immune processes in chronic pain biology.
Although rare coding variants explained a modest proportion of the overall variation in chronic pain susceptibility, their average effects were larger in the most damaging functional categories. This was particularly evident for high confidence loss of function variants, which can substantially disrupt gene function.
Genetic correlation analyses further revealed shared genetic components across chronic pain conditions, alongside positive correlations with selected psychiatric and nervous system disorders. These findings suggest that some biological influences may be shared across different pain phenotypes and other conditions.
The findings provide a broader map of coding variation associated with chronic pain, while highlighting the potential value of rare variants in identifying specific genes and biological mechanisms. The implicated pathways include neuronal development, neuroimmune signalling and tissue homeostasis.
However, the study does not establish that the identified variants directly cause chronic pain or demonstrate their clinical utility for diagnosis or treatment. Further investigation is needed to validate the proposed mechanisms experimentally and assess whether the findings apply across populations with different ancestries.
The researchers concluded that these results provide a foundation for future multi ancestry studies and functional validation, which may help clarify the biological basis of chronic pain and inform subsequent research into its underlying mechanisms.
Reference
Ao X et al. Exome-wide association study reveals common and rare coding variants shaping chronic pain in 327,642 UK Biobank participants. Genome Med. 2026;18(1):156.
Featured Image: chinnarach on Adobe Stock
Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.
