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. 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, 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 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 COPC via cortico-limbic circuits.

Spinal TRPA1 Contributes to the Mechanical Hypersensitivity Effect Induced by Netrin-1

“…The hypersensitivity effect is submodality-selective as shown by the finding that netrin-1 did not influence heat nociception. The hypersensitivity effect of netrin-1 in the present study is in line with earlier results reporting that netrin-1 is associated with pain in various experimental and pathophysiological conditions [ 5 , 6 , 7 , 8 , 9 , 13 ] and that the DCC receptor, a key mediator of attractive signaling by netrin-1 [ 2 ], may be mediating pronociceptive effects of netrin-1 [ 5 , 6 , 7 , 11 , 13 ]. The present study extends earlier findings by showing that a single intrathecal dose of netrin-1 does not only induce acute hypersensitivity in rodents [ 7 ], but it may induce a prolonged neuropathy-like pain hypersensitivity condition lasting at least up to three weeks.…”

“…In addition, human studies have reported that in patients with endometriosis, netrin-1 and DCC levels are increased in endometrial tissues [ 11 ], and patients with small fiber neuropathy have increased netrin-1 gene expression in keratinocytes [ 12 ]. In genome-wide analysis, the DCC netrin-1 receptor gene was identified as the top gene associated with multisite pain [ 13 ].…”

Identification and characterization of genetic risk shared across 24 chronic pain conditions in the UK Biobank

“…Genetic overlap with non-pain conditions was suggestive of the complexity of factors contributing to chronic pain. Furthermore, DCC , the top gene associated with F1, was also the top gene reported in a recent study of chronic overlapping pain conditions (COPCs), which used pain for more than 3 months in different body sites from the UKBB (head, face, neck/shoulder, back, stomach, hip, knee, all over the body) [59]. Of the 241 genes mapped to independent significant SNPs from the F1 GWAS, FKBP5 was the only one previously targeted in a candidate gene study (as opposed to GWAS) for posttraumatic musculoskeletal pain [144, 10].…”

“…The UKBB is a large and extensively phenotyped cohort, which recently added First Occurrences data (category 1712), giving researchers access to primary care and death register records to supplement self-reports and ICD-10 diagnoses, earlier available exclusively from hospital intake records. This growing trove of genotypic and phenotypic data has enabled us to examine a much larger number of pain conditions than reported in prior genetic studies of multi-site pain [58, 56, 59, 120]. Our work builds on earlier studies, which included smaller numbers of conditions, often selected a priori based on anatomic proximity or hypothesized etiology.…”

“…Similar approaches have emerged in pain research, informed by studies of the co-occurrence of pain conditions in large samples [105, 113, 66, 72, 3] and the recognition that different forms of pain are related to similar alterations in the nervous system [65, 76, 54, 63]. Some studies have examined genetic correlations among pain syndromes [129] and genetic risks of having pain in more than 1 of 7 locations on the body [56, 59]. However, a systematic assessment of shared susceptibility across a broad spectrum of pain conditions is lacking, and common factors underlying general pain susceptibility have not yet been characterized.…”