• Mikael Åkerlund, Georgios Baskozos, Wenqianglong Li, Andreas C Themistocleous, Mathilde M V Pascal, N William Rayner, Nadine Attal, Ralf Baron, Sophie Baudic, Kristine Bennedsgaard, Didier Bouhassira, Maddalena Comini, Geert Crombez, Catharina G Faber, Nanna B Finnerup, Janne Gierthmühlen, Yelena Granovsky, Sandra Sif Gylfadottir, Harry L Hébert, Troels S Jensen, Jishi John, Harriet I Kemp, Giuseppe Lauria, Helen Laycock, Weihua Meng, Kristian Bernhard Nilsen, Colin Palmer, RiceAndrew S CASCPain Research, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom., Jordi Serra, Blair H Smith, Solomon Tesfaye, Leah Shafran Topaz, Abirami Veluchamy, Jan Vollert, David Yarnitsky, Natalie van Zuydam, John Anker Zwart, Mark I McCarthy, Valeriya Lyssenko, and David L Bennett.
• Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Lund, Sweden.
• Pain. 2024 Oct 29.

AbstractWe 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.Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.

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