Genetic associations of neuropathic pain and sensory profile in a deeply phenotyped neuropathy cohort
(2024) In Pain- Abstract
We aimed to investigate the genetic associations of neuropathic pain in a deeply phenotyped cohort. Participants with neuropathic pain were cases and compared with those exposed to injury or disease but without neuropathic pain as control subjects. Diabetic polyneuropathy was the most common aetiology of neuropathic pain. A standardised quantitative sensory testing protocol was used to categorize participants based on sensory profile. We performed genome-wide association study, and in a subset of participants, we undertook whole-exome sequencing targeting analyses of 45 known pain-related genes. In the genome-wide association study of diabetic neuropathy (N 5 1541), a top significant association was found at the KCNT2 locus linked with... (More)
We aimed to investigate the genetic associations of neuropathic pain in a deeply phenotyped cohort. Participants with neuropathic pain were cases and compared with those exposed to injury or disease but without neuropathic pain as control subjects. Diabetic polyneuropathy was the most common aetiology of neuropathic pain. A standardised quantitative sensory testing protocol was used to categorize participants based on sensory profile. We performed genome-wide association study, and in a subset of participants, we undertook whole-exome sequencing targeting analyses of 45 known pain-related genes. In the genome-wide association study of diabetic neuropathy (N 5 1541), a top significant association was found at the KCNT2 locus linked with pain intensity (rs114159097, P 5 3.55 3 1028). Gene-based analysis revealed significant associations between LHX8 and TCF7L2 and neuropathic pain. Polygenic risk score for depression was associated with neuropathic pain in all participants. Polygenic risk score for C-reactive protein showed a positive association, while that for fasting insulin showed a negative association with neuropathic pain, in individuals with diabetic polyneuropathy. Gene burden analysis of candidate pain genes supported significant associations between rare variants in SCN9A and OPRM1 and neuropathic pain. Comparison of individuals with the “irritable” nociceptor profile to those with a “nonirritable” nociceptor profile identified a significantly associated variant (rs72669682, P 5 4.39 3 1028) within the ANK2 gene. Our study on a deeply phenotyped cohort with neuropathic pain has confirmed genetic associations with the known pain-related genes KCNT2, OPRM1, and SCN9A and identified novel associations with LHX8 and ANK2, genes not previously linked to pain and sensory profiles, respectively.
(Less)
- author
- organization
- publishing date
- 2024
- type
- Contribution to journal
- publication status
- epub
- subject
- keywords
- Diabetes mellitus, GWAS, Neuropathic pain, Neuropathy, SCN9A, Sensory profile
- in
- Pain
- publisher
- Elsevier
- external identifiers
-
- pmid:39471050
- scopus:85208221634
- ISSN
- 0304-3959
- DOI
- 10.1097/j.pain.0000000000003463
- language
- English
- LU publication?
- yes
- id
- 01328ac4-e7db-4808-a8f1-9f440aafd2d7
- date added to LUP
- 2024-12-11 09:56:29
- date last changed
- 2025-06-12 03:00:03
@article{01328ac4-e7db-4808-a8f1-9f440aafd2d7,
abstract = {{<p>We aimed to investigate the genetic associations of neuropathic pain in a deeply phenotyped cohort. Participants with neuropathic pain were cases and compared with those exposed to injury or disease but without neuropathic pain as control subjects. Diabetic polyneuropathy was the most common aetiology of neuropathic pain. A standardised quantitative sensory testing protocol was used to categorize participants based on sensory profile. We performed genome-wide association study, and in a subset of participants, we undertook whole-exome sequencing targeting analyses of 45 known pain-related genes. In the genome-wide association study of diabetic neuropathy (N 5 1541), a top significant association was found at the KCNT2 locus linked with pain intensity (rs114159097, P 5 3.55 3 10<sup>28</sup>). Gene-based analysis revealed significant associations between LHX8 and TCF7L2 and neuropathic pain. Polygenic risk score for depression was associated with neuropathic pain in all participants. Polygenic risk score for C-reactive protein showed a positive association, while that for fasting insulin showed a negative association with neuropathic pain, in individuals with diabetic polyneuropathy. Gene burden analysis of candidate pain genes supported significant associations between rare variants in SCN9A and OPRM1 and neuropathic pain. Comparison of individuals with the “irritable” nociceptor profile to those with a “nonirritable” nociceptor profile identified a significantly associated variant (rs72669682, P 5 4.39 3 10<sup>28</sup>) within the ANK2 gene. Our study on a deeply phenotyped cohort with neuropathic pain has confirmed genetic associations with the known pain-related genes KCNT2, OPRM1, and SCN9A and identified novel associations with LHX8 and ANK2, genes not previously linked to pain and sensory profiles, respectively.</p>}},
author = {{Akerlund, Mikael and Baskozos, Georgios and Li, Wenqianglong and Themistocleous, Andreas C. and Pascal, Mathilde M.V. and Rayner, N. William and Attal, Nadine and Baron, Ralf and Baudic, Sophie and Bennedsgaard, Kristine and Bouhassira, Didier and Comini, Maddalena and Crombez, Geert and Faber, Catharina G. and Finnerup, Nanna B. and Gierthmühlen, Janne and Granovsky, Yelena and Gylfadottir, Sandra Sif and Hébert, Harry L. and Jensen, Troels S. and John, Jishi and Kemp, Harriet I. and Lauria, Giuseppe and Laycock, Helen and Meng, Weihua and Nilsen, Kristian Bernhard and Palmer, Colin and Rice, Andrew S.C. and Serra, Jordi and Smith, Blair H. and Tesfaye, Solomon and Topaz, Leah Shafran and Veluchamy, Abirami and Vollert, Jan and Yarnitsky, David and van Zuydam, Natalie and Zwart, John Anker and McCarthy, Mark I. and Lyssenko, Valeriya and Bennett, David L.}},
issn = {{0304-3959}},
keywords = {{Diabetes mellitus; GWAS; Neuropathic pain; Neuropathy; SCN9A; Sensory profile}},
language = {{eng}},
publisher = {{Elsevier}},
series = {{Pain}},
title = {{Genetic associations of neuropathic pain and sensory profile in a deeply phenotyped neuropathy cohort}},
url = {{http://dx.doi.org/10.1097/j.pain.0000000000003463}},
doi = {{10.1097/j.pain.0000000000003463}},
year = {{2024}},
}