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. 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.

• Authors: Samar Khoury, Marc Parisien, Scott J Thompson, Etienne Vachon-Presseau, Mathieu Roy, Amy E Martinsen, Bendik S Winsvold, HUNT All-In Pain, Ingunn P Mundal, John-Anker Zwart, Artur Kania, Jeffrey S Mogil, Luda Diatchenko
• Journal: Brain : a journal of neurology (Brain) Vol. 145 Issue 3 Pg. 1111-1123 (04 29 2022) ISSN: 1460-2156 [Electronic] England
• PMID: 34788396 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Netrin-1

Topics

• Brain (diagnostic imaging)
• Chronic Disease
• Chronic Pain (genetics)
• Humans
• Netrin-1
• Neurogenesis (genetics)
• White Matter