Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom.
Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
JAMA Netw Open. 2021 Dec 1;4(12):e2136560. doi: 10.1001/jamanetworkopen.2021.36560.
Neuropathic pain (NP) has important clinical and socioeconomic consequences for individuals and society. Increasing evidence indicates that genetic factors make a significant contribution to NP, but genome-wide association studies (GWASs) are scant in this field and could help to elucidate susceptibility to NP.
To identify genetic variants associated with NP susceptibility.
DESIGN, SETTING, AND PARTICIPANTS: This genetic association study included a meta-analysis of GWASs of NP using 3 independent cohorts: ie, Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS); Generation Scotland: Scottish Family Health Study (GS:SFHS); and the United Kingdom Biobank (UKBB). Data analysis was conducted from April 2018 to December 2019.
Individuals with NP (ie, case participants; those with pain of ≥3 months' duration and a Douleur Neuropathique en 4 Questions score ≥3) and individuals with no pain (ie, control participants) with or without diabetes from GoDARTS and GS:SFHS were identified using validated self-completed questionnaires. In the UKBB, self-reported prescribed medication and hospital records were used as a proxy to identify case participants (patients recorded as receiving specific anti-NP medicines) and control participants.
GWAS was performed using linear mixed modeling. GWAS summary statistics were combined using fixed-effect meta-analysis. A total of 51 variants previously shown to be associated with NP were tested for replication.
This study included a total of 4512 case participants (2662 [58.9%] women; mean [SD] age, 61.7 [10.8] years) and 428 489 control participants (227 817 [53.2%] women; mean [SD] age, 62.3 [11.5] years) in the meta-analysis of 3 cohorts with European descent. The study found a genome-wide significant locus at chromosome 12q23.1, which mapped to SLC25A3 (rs369920026; odds ratio [OR] for having NP, 1.68; 95% CI, 1.40-2.02; P = 1.30 × 10-8), and a suggestive variant at 13q14.2 near CAB39L (rs7992766; OR, 1.09; 95% CI, 1.05-1.14; P = 1.22 × 10-7). These mitochondrial phosphate carriers and calcium binding genes are expressed in brain and dorsal root ganglia. Colocalization analyses using expression quantitative loci data found that the suggestive variant was associated with expression of CAB39L in the brain cerebellum (P = 1.01 × 10-14). None of the previously reported variants were replicated.
To our knowledge, this was the largest meta-analyses of GWAS to date. It found novel genetic variants associated with NP susceptibility. These findings provide new insights into the genetic architecture of NP and important information for further studies.
神经病理性疼痛 (NP) 给个人和社会带来了重要的临床和社会经济后果。越来越多的证据表明，遗传因素对 NP 有重要贡献，但该领域的全基因组关联研究 (GWAS) 很少，这可能有助于阐明对 NP 的易感性。
确定与 NP 易感性相关的遗传变异。
设计、设置和参与者：本遗传关联研究使用三个独立队列的 NP GWAS 进行了荟萃分析：即苏格兰泰赛德糖尿病审计和研究遗传学 (GoDARTS)；苏格兰家族健康研究的世代 (GS:SFHS)；和英国生物库 (UKBB)。数据分析于 2018 年 4 月至 2019 年 12 月进行。
使用经过验证的自我完成问卷，从 GoDARTS 和 GS:SFHS 中确定 NP 患者 (即有疼痛≥3 个月且 4 个问题疼痛问卷评分≥3 的患者) 和无疼痛患者 (即有或没有糖尿病的对照参与者)。在 UKBB 中，自我报告的处方药物和医院记录被用作识别病例参与者 (记录为接受特定抗 NP 药物的患者) 和对照参与者的代理。
使用线性混合模型进行 GWAS。使用固定效应荟萃分析合并 GWAS 汇总统计数据。总共测试了 51 个先前与 NP 相关的变异，以进行复制。
本研究共纳入了 4512 名病例参与者 (2662 [58.9%] 名女性；平均 [标准差] 年龄 61.7 [10.8] 岁) 和 428489 名对照参与者 (227817 [53.2%] 名女性；平均 [标准差] 年龄 62.3 [11.5] 岁)，进行了 3 个欧洲裔队列的荟萃分析。研究在 12 号染色体 q23.1 发现了一个全基因组显著的基因座，该基因座映射到 SLC25A3 (rs369920026；患 NP 的优势比 [OR]，1.68；95%置信区间 [CI]，1.40-2.02；P = 1.30×10-8)，在 13 号染色体 q14.2 附近的 CAB39L 附近发现了一个提示性变体(rs7992766；OR，1.09；95%CI，1.05-1.14；P = 1.22×10-7)。这些线粒体磷酸盐载体和钙结合基因在大脑和背根神经节中表达。使用表达定量基因座数据的共定位分析发现，提示性变体与大脑小脑中的 CAB39L 表达相关 (P = 1.01×10-14)。先前报道的变异均未被复制。
据我们所知，这是迄今为止对 GWAS 的最大荟萃分析。它发现了与 NP 易感性相关的新遗传变异。这些发现为 NP 的遗传结构提供了新的见解，并为进一步的研究提供了重要信息。
