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

Abstract

Chronic pain is often present at more than one anatomical location, leading to chronic overlapping pain conditions (COPC). Whether COPC represents 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 vs. multi-site pain in the UK Biobank. We found that different genetic signals underlie chronic single-site and multi-site pain with much stronger genetic contributions for the latter. Among 23 loci associated with multi-site pain, 9 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 multi-site 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 COPC via cortico-limbic circuits.