Abstract
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. 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.
Highlights
Neuropathic pain (NP) arises as a consequence of a lesion or disease affecting the somatosensory nervous system[1] and affects 7% to 10% of the general population.[2]
The study found a genome-wide significant locus at chromosome 12q23.1, which mapped to SLC25A3, and a suggestive variant at 13q14.2 near CAB39L
To our knowledge, this was the largest meta-analyses of genome-wide association studies (GWASs) 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
Summary
Neuropathic pain (NP) arises as a consequence of a lesion or disease affecting the somatosensory nervous system[1] and affects 7% to 10% of the general population.[2]. Not every patient who has an underlying relevant disease develops NP; for example, as many as 26% of individuals with diabetes were found to have NP.[9,10] It is likely that genetic factors play a role in the risk of developing NP.[11]
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