Background 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 five 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. Methods 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 eight variant-to-gene criteria to identify putative causal genes. Results We identified seven 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 (four) 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. Discussion 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.

MDT, RP, ATW, FD and NS received funding from Orion Pharma within the scope of the submitted work. WH, and MM are salaried employees of Orion Pharma within the scope of the submitted work. RB and BR were previously salaried employees of Orion within the scope of this work; BR is now a salaried employee of AstraZeneca.

MDT, RP, ATW, FD and NS received funding from Orion Pharma within the scope of the submitted work. WH, and MM are salaried employees of Orion Pharma within the scope of the submitted work. RB and BR were previously salaried employees of Orion within the scope of this work; BR is now a salaried employee of AstraZeneca.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All data was obtained from the UK Biobank study under application 43027. UK Biobank has ethical approval from the UK National Health Service National Research Ethics Service (11/NW/0382), and informed consent was obtained from all participants.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data was obtained from the UK Biobank study. Code to reproduce the pain phenotypes can be obtained using the DeepPheWAS R package (https://github.com/Richard-Packer/DeepPheWAS)