Association of Genetic Variant at Chromosome 12q23.1 With Neuropathic Pain Susceptibility

Abirami Veluchamy, Harry L Hébert, Natalie R van Zuydam, Ewan R Pearson, Archie Campbell, Caroline Hayward, Weihua Meng, Mark I McCarthy, David L H Bennett, Colin N A Palmer, Blair H Smith

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)e2136560
JournalJAMA Network Open
Volume4
Issue number12
DOIs
Publication statusPublished - 1 Dec 2021

Keywords

  • Aged
  • Case-Control Studies
  • Chromosomes, Human, Pair 12/genetics
  • Female
  • Genetic Association Studies
  • Genetic Loci/genetics
  • Genetic Predisposition to Disease/genetics
  • Humans
  • Linear Models
  • Male
  • Middle Aged
  • Neuralgia/genetics
  • Odds Ratio
  • Polymorphism, Single Nucleotide/genetics
  • United Kingdom
  • Whites/genetics

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