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

Khoury, Samar; Parisien, Marc; Thompson, Scott J.; Vachon-Presseau, Etienne; Roy, Mathieu; Mitchell, Amy; Winsvold, Bendik K S; Skogholt, Anne Heidi; Brumpton, Ben Michael; Willer, Cristen J.; Fors, Egil Andreas; Heuch, Ingrid; Nielsen, Jonas Bille; Storheim, Kjersti; Hagen, Knut; Nilsen, Kristian Bernhard; Hveem, Kristian; Fritsche, Lars; Thomas, Laurent; Pedersen, Linda Margareth; Gabrielsen, Maiken Elvestad; Johnsen, Marianne Bakke; Lie, Marie; Holmen, Oddgeir; Børte, Sigrid; Stensland, Synne; Zhou, Wei; Mundal, Ingunn Pernille; Zwart, John Anker Henrik; Kania, Artur; Mogil, Jeffrey S.; Diatchenko, Luda
Peer reviewed, Journal article
Accepted version
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URI
https://hdl.handle.net/11250/2988121
Date
2021
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  • Fakultet for medisin og helsevitenskap (uspesifisert) [989]
  • Institutt for klinisk og molekylær medisin [3849]
  • Institutt for nevromedisin og bevegelsesvitenskap [3578]
  • Institutt for samfunnsmedisin og sykepleie [4108]
  • Publikasjoner fra CRIStin - NTNU [41954]
Original version
Brain. 2021, .   10.1093/brain/awab359
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. Keywords: chronic overlapping pain conditions, netrin, uncinate fasciculus
Publisher
Oxford University Press
Journal
Brain
Copyright
This is the authors' accepted manuscript to the article. Locked until 11/11-2022 due to copyright restrictions. The version of record is available online at: https://doi.org/10.1093/brain/awab359

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