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Åkerlund, M.* ; Baskozos, G.* ; Li, W.* ; Themistocleous, A.C.* ; Pascal, M.M.V.* ; Rayner, N.W. ; Attal, N.* ; Baron, R.* ; Baudic, S.* ; Bennedsgaard, K.* ; Bouhassira, D.* ; Comini, M.* ; Crombez, G.* ; Faber, C.G.* ; Finnerup, N.B.* ; Gierthmühlen, J.* ; Granovsky, Y.* ; Gylfadottir, S.S.* ; Hébert, H.L.* ; Jensen, T.S.* ; John, J.* ; Kemp, H.I.* ; Lauria, G.* ; Laycock, H.* ; Meng, W.* ; Nilsen, K.B.* ; Palmer, C.* ; Rice, A.S.C.* ; Serra, J.* ; Smith, B.H.* ; Tesfaye, S.* ; Topaz, L.S.* ; Veluchamy, A.* ; Vollert, J.* ; Yarnitsky, D.* ; van Zuydam, N.* ; Zwart, J.A.* ; McCarthy, M.I.* ; Lyssenko, V.* ; Bennett, D.L.*

Genetic associations of neuropathic pain and sensory profile in a deeply phenotyped neuropathy cohort.

Pain 166, 1354-1368 (2024)
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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 = 1541), a top significant association was found at the KCNT2 locus linked with pain intensity (rs114159097, P = 3.55 × 10-8). 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 = 4.39 × 10-8) 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Diabetes Mellitus ; Gwas ; Neuropathic Pain ; Neuropathy ; Scn9a ; Sensory Profile; Genome-wide Association; Opioid Receptor; Sodium-channels; Scn9a Variants; Mutation; Protein; Symptoms; Tcf7l2
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 0304-3959
e-ISSN 1872-6623
Journal Pain
Quellenangaben Volume: 166, Issue: 6, Pages: 1354-1368 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Translational Genomics (ITG)
POF-Topic(s) 30205 - Bioengineering and Digital Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-506700-001
Grants Wellcome Trust
DOI 10.1097/j.pain.0000000000003463
WOS ID 001486839400006
Scopus ID 85208221634
PubMed ID 39471050
Erfassungsdatum 2024-10-30
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