Åkerlund Mikael, Baskozos Georgios, Li Wenqianglong, Themistocleous Andreas C, Pascal Mathilde M V, Rayner N William, Attal Nadine, Baron Ralf, Baudic Sophie, Bennedsgaard Kristine, Bouhassira Didier, Comini Maddalena, Crombez Geert, Faber Catharina G, Finnerup Nanna B, Gierthmühlen Janne, Granovsky Yelena, Gylfadottir Sandra Sif, Hébert Harry L, Jensen Troels S, John Jishi, Kemp Harriet I, Lauria Giuseppe, Laycock Helen, Meng Weihua, Nilsen Kristian Bernhard, Palmer Colin, Rice Andrew S C, Serra Jordi, Smith Blair H, Tesfaye Solomon, Topaz Leah Shafran, Veluchamy Abirami, Vollert Jan, Yarnitsky David, van Zuydam Natalie, Zwart John Anker, McCarthy Mark I, Lyssenko Valeriya, Bennett David L
Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Lund, Sweden.
Nuffield Department of Clinical Neuroscience, The University of Oxford, Oxford, United Kingdom.
Pain. 2025 Jun 1;166(6):1354-1368. doi: 10.1097/j.pain.0000000000003463. Epub 2024 Oct 29.
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.
我们旨在研究一个深度表型队列中神经性疼痛的遗传关联。患有神经性疼痛的参与者为病例组，并与暴露于损伤或疾病但无神经性疼痛的参与者作为对照进行比较。糖尿病性多发性神经病是神经性疼痛最常见的病因。使用标准化的定量感觉测试方案根据感觉特征对参与者进行分类。我们进行了全基因组关联研究，并且在一部分参与者中，我们对45个已知的疼痛相关基因进行了全外显子测序靶向分析。在糖尿病性神经病的全基因组关联研究（N = 1541）中，在与疼痛强度相关的KCNT2基因座发现了一个高度显著的关联（rs114159097，P = 3.55×10 -8）。基于基因的分析揭示了LHX8和TCF7L2与神经性疼痛之间的显著关联。抑郁的多基因风险评分与所有参与者的神经性疼痛相关。在患有糖尿病性多发性神经病的个体中，C反应蛋白的多基因风险评分与神经性疼痛呈正相关，而空腹胰岛素的多基因风险评分与神经性疼痛呈负相关。候选疼痛基因的基因负担分析支持SCN9A和OPRM1中的罕见变异与神经性疼痛之间的显著关联。将具有“易激惹”伤害感受器特征的个体与具有“非易激惹”伤害感受器特征的个体进行比较，在ANK2基因内发现了一个显著相关的变异（rs72669682，P = 4.39×10 -8）。我们对一个具有深度表型的神经性疼痛队列的研究证实了与已知疼痛相关基因KCNT2、OPRM1和SCN9A的遗传关联，并分别鉴定了与LHX8和ANK2的新关联，这两个基因以前分别与疼痛和感觉特征无关。
