Genome-wide analysis identifies impaired axonogenesis in chronic overlapping pain conditions

Chronic pain is often present at more than one anatomical location, leading to chronic overlapping pain conditions. Whether chronic overlapping pain conditions represent a distinct pathophysiology from the occurrence of pain at only one site is unknown. Using genome-wide approaches, we compared genetic determinants of chronic single-site versus multisite pain in the UK Biobank. We found that different genetic signals underlie chronic single-site and multisite pain with much stronger genetic contributions for the latter. Among 23 loci associated with multisite pain, nine loci replicated in the HUNT cohort, with the DCC netrin 1 receptor (DCC) as the top gene. Functional genomics identified axonogenesis in brain tissues as the major contributing pathway to chronic multisite pain. Finally, multimodal structural brain imaging analysis showed that DCC is most strongly expressed in subcortical limbic regions and is associated with alterations in the uncinate fasciculus microstructure, suggesting that DCC-dependent axonogenesis may contribute to chronic overlapping pain conditions via corticolimbic circuits.

Automated summary

Research has found that chronic multisite pain and chronic single-site pain have different genetic determinants. The genetic contributions are stronger for chronic multisite pain compared to chronic single-site pain. Functional genomics and brain imaging analysis suggest that axonogenesis plays a significant role in brain tissues and the gene DCC, which is associated with chronic multisite pain, is predominantly expressed in subcortical limbic regions and affects the microstructure of the uncinate fasciculus.