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Genetic associations of neuropathic pain and sensory profile in a deeply phenotyped neuropathy cohort.
Pain ( IF 5.9 ) Pub Date : 2024-10-29 , DOI: 10.1097/j.pain.0000000000003463 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,Andrew S C Rice,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,David L Bennett
Pain ( IF 5.9 ) Pub Date : 2024-10-29 , DOI: 10.1097/j.pain.0000000000003463 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,Andrew S C Rice,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,David L Bennett
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.
中文翻译：
深度表型神经病变队列中神经性疼痛和感觉特征的遗传关联。
我们旨在研究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是病例，并与那些暴露于损伤或疾病但没有神经性疼痛的参与者作为对照受试者进行比较。糖尿病性多发性神经病是神经性疼痛的最常见病因。使用标准化的定量感官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，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组测序靶向分析。在糖尿病神经病变的全基因组关联研究 （N = 1541） 中，发现与疼痛强度相关的 KCNT2 基因座存在最显著的关联 （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着关联。抑郁症的多基因风险评分与所有参与者的神经性疼痛相关。在糖尿病性多发性神经病患者中，C 反应蛋白的多基因风险评分显示呈正相关，而空腹胰岛素的评分显示与神经性疼痛呈负相关。候选疼痛基因的基因负荷分析支持 SCN9A 和 OPRM1 的罕见变异与神经性疼痛之间的显着关联。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，发现 ANK2 基因中存在显着相关的变异 （rs72669682，P = 4.39 × 10-8）。 我们对神经性疼痛的深度表型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，并确定了与 LHX8 和 ANK2 的新关联，这些基因以前分别与疼痛和感觉特征无关。
更新日期：2024-10-29
中文翻译：
深度表型神经病变队列中神经性疼痛和感觉特征的遗传关联。
我们旨在研究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是病例，并与那些暴露于损伤或疾病但没有神经性疼痛的参与者作为对照受试者进行比较。糖尿病性多发性神经病是神经性疼痛的最常见病因。使用标准化的定量感官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，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组测序靶向分析。在糖尿病神经病变的全基因组关联研究 （N = 1541） 中，发现与疼痛强度相关的 KCNT2 基因座存在最显著的关联 （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着关联。抑郁症的多基因风险评分与所有参与者的神经性疼痛相关。在糖尿病性多发性神经病患者中，C 反应蛋白的多基因风险评分显示呈正相关，而空腹胰岛素的评分显示与神经性疼痛呈负相关。候选疼痛基因的基因负荷分析支持 SCN9A 和 OPRM1 的罕见变异与神经性疼痛之间的显着关联。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，发现 ANK2 基因中存在显着相关的变异 （rs72669682，P = 4.39 × 10-8）。 我们对神经性疼痛的深度表型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，并确定了与 LHX8 和 ANK2 的新关联，这些基因以前分别与疼痛和感觉特征无关。
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