Abstract
ABSTRACT: Neuropathic pain is a common and debilitating symptom with limited treatment options. Genetic studies, which can provide vital evidence for drug development, have identified only 3 genome-wide significant signals for neuropathic pain traits. To address this, we performed the largest genome-wide association study (GWAS) to date of all-cause neuropathic pain and neuropathic pain subtypes. We defined all-cause neuropathic pain and 33 neuropathic pain subtypes using DeepPheWAS software in the UK Biobank, taking advantage of the longitudinal drug prescription data alongside clinical and self-reported records. We performed a GWAS of all-cause neuropathic pain (33,278 cases, 140,134 controls) as our primary analysis and GWASs of neuropathic pain subtypes as secondary analyses. We used 8 variant-to-gene criteria to identify putative causal genes. We identified 7 independent novel genome-wide associations for neuropathic pain phenotypes, which mapped to 22 novel putative causal genes. NCAM1 was the only gene identified from the primary analysis of all-cause neuropathic pain and met the most variant-to-gene criteria (4) of any identified gene. Of the 21 other genes, ASCC1, CHST3, C4A/C4B , and KCNN2 had the most compelling evidence for mechanistic involvement in neuropathic pain. We have performed the largest GWAS to date of all-cause neuropathic pain and more than doubled the number of genome-wide significant associations for neuropathic pain traits, identifying putative causal genes. There is strong evidence for the involvement of NCAM1 in neuropathic pain, which merits for further study for drug development.