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- Title
Association of Genetic Variant at Chromosome 12q23.1 With Neuropathic Pain Susceptibility.
- Authors
Veluchamy, Abirami; Hébert, Harry L.; van Zuydam, Natalie R.; Pearson, Ewan R.; Campbell, Archie; Hayward, Caroline; Meng, Weihua; McCarthy, Mark I.; Bennett, David L. H.; Palmer, Colin N. A.; Smith, Blair H.
- Abstract
Key Points: Question: Are genetic variants associated with neuropathic pain (NP) susceptibility? Findings: This genetic association study included a meta-analysis of 3 genome-wide association studies, with 4512 individuals with NP and 428 489 without, all with European descent, and identified a novel genome-wide significant locus at chromosome 12q23.1 near SLC25A3 and a suggestive locus at chromosome 13q14.2 near CAB39L. These mitochondrial phosphate carriers and calcium binding genes are expressed in tissues associated with the generation of NP, including the brain and dorsal root ganglia. Meaning: These findings may provide a better understanding of genetic predisposition to NP, and this may inform the development of new treatment strategies. This genetic association study identifies genetic variants associated with neuropathic pain. Importance: 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. Objective: 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. Exposures: 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. Main Outcomes and Measures: 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. Results: 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. Conclusions and Relevance: 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.
- Subjects
CONFIDENCE intervals; META-analysis; NEURALGIA; GENETIC variation; KERATOSIS follicularis; CEREBELLUM; DISEASE susceptibility; QUESTIONNAIRES; MEDICAL records; CHROMOSOME abnormalities; DESCRIPTIVE statistics; GENOTYPES; SPINAL nerve roots; RESEARCH funding; ODDS ratio; DATA analysis software; CALCIUM-binding proteins; PHENOTYPES; DISEASE risk factors
- Publication
JAMA Network Open, 2021, Vol 4, Issue 12, pe2136560
- ISSN
2574-3805
- Publication type
Article
- DOI
10.1001/jamanetworkopen.2021.36560