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

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

doi:10.1093/brain/awab359

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

Brain. 2022 Apr 29;145(3):1111-1123. doi: 10.1093/brain/awab359.

Authors

Samar Khoury^{1

2

3}, Marc Parisien^{1

2

3}, Scott J Thompson^{1

4}, Etienne Vachon-Presseau^{1

2

3}, Mathieu Roy^{1

5}, Amy E Martinsen^{6

7

8}, Bendik S Winsvold^{6

7

9}; HUNT All-In Pain; Ingunn P Mundal¹⁰, John-Anker Zwart^{6

7

8}, Artur Kania^{11

12}, Jeffrey S Mogil^{1

5}, Luda Diatchenko^{1

2

3}

Affiliations

¹ Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC H3A 0G1, Canada.
² Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC H3A 0G1, Canada.
³ Department of Anesthesia, Faculty of Medicine, McGill University, Montreal, QC H3A 0G1, Canada.
⁴ Department of Anesthesiology, University of Minnesota, Minneapolis, MN 55455, USA.
⁵ Department of Psychology, McGill University, Montreal, QC H3A 0G1, Canada.
⁶ K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim 7491, Norway.
⁷ Division of Clinical Neuroscience, Department of Research, Innovation and Education, Oslo University Hospital, Oslo 0424, Norway.
⁸ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo 0318, Norway.
⁹ Department of Neurology, Oslo University Hospital, Oslo 0424, Norway.
¹⁰ Department of Health Science, Molde University College, Molde 6410, Norway.
¹¹ Institut de recherches cliniques de Montreal (IRCM), Montreal, QC H2W 1R7, Canada.
¹² Department of Cell Biology and Anatomy, and Experimental Medicine, McGill University, Montreal, QC H3A 0G1, Canada.

PMID: 34788396
DOI: 10.1093/brain/awab359

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.

Keywords: chronic overlapping pain conditions; netrin; uncinate fasciculus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Brain / diagnostic imaging
Chronic Disease
Chronic Pain* / genetics
Humans
Netrin-1
Neurogenesis / genetics
White Matter*

Substances

Netrin-1

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

Authors

Collaborators

Affiliations

Abstract

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MeSH terms

Substances

Grants and funding