Figure 1.

The contribution of axonogenesis to chronic overlapping pain conditions based on the results from genome-wide association studies and brain imaging data (based on Khoury et al).³⁵ Genome-wide association studies were conducted in human subjects reporting chronic pain at a single body site (N = 1 site, blue) or multiple body sites (N ≥ 2 sites, purple), compared with human subjects not reporting any pain (N = 0). The DCC Netrin 1 Receptor (also known as colorectal cancer suppressor) gene was found to be strongly associated with multisite chronic pain but not with single-site chronic pain. DCC is a gene that critically contributes to axonogenesis, the process of steered development of neuronal axons toward their synaptic targets. Consistent with the association of DCC gene with chronic multisite pain, the genome-wide association study-based pathways analyses identified axonogenesis in brain tissues as the major contributing pathway to chronic multisite pain. Genetic partitioned heritability (h²) analysis indicated a significant enrichment of heritability in single-nucleotide polymorphisms at loci of genes exclusively expressed in brain regions for multisite chronic pain but not for single-site chronic pain. Brain imaging data identified increased neurite orientation dispersion with an increased number of chronic pain sites. The orientation dispersion of neurites can range from highly parallel (coherently oriented white matter structures) to highly dispersed (grey matter structures characterized by sprawlig dendritic processes in all directions), as suggested by the neuronal networks inside the bar plot's bars. Orientation dispersion is shown for the uncinate fasciculus brain sub-structure. The background brain image shows evidence for DCC expression in the uncinate fasciculus. Together, our results suggest that genetically determined DCC-dependent disorganization in axonal tracks in patients with chronic overlapping pain conditions may contribute to pathogenesis of disease through corticolimbic circuits.