Carriers ofSCN9Avariants linked to inherited and acquired pain syndromes show no alteration in the prevalence of pain or analgesic usage in the UK Biobank cohort

Abstract The voltage-gated sodium channel NaV1.7, encoded by the SCN9A gene, is integral to nociceptor excitability and pain sensation. Multiple gain-of-function SCN9A variants have been reported to cause autosomal dominant painful channelopathies, including primary erythromelalgia and paroxysmal extreme pain disorder, and they have been linked to the pathogenesis of painful small fibre neuropathies. The prevalence and impact on carriers of these gain-of-function NaV1.7 variants in the wider population has yet to be explored. A literature search was performed to identify pathogenic SCN9A variants linked to painful channelopathies. SCN9A variants that were associated with small fibre neuropathy were also included if they had in vitro electrophysiological evidence of gain-of-function. We investigated the prevalence of these SCN9A variants in the UK Biobank cohort (using the 470K whole-exome sequencing dataset). Logistic regression was used to examine whether carrying pathogenic variants was associated with chronic pain, neuropathic pain, and analgesic or anti-neuropathic drug prescription (adjusting for age, sex, and the first 10 genetic principal components). A total of 59 putative pathogenic gain-of-function variants in SCN9A were identified from the literature review, of which 20 were found in the UK Biobank cohort (in over 148,000 carriers, >29%). Logistic regression analysis was feasible for 11 of the 20 variants which each had ≥50 heterozygous carriers and were not in linkage disequilibrium with another putative pathogenic mutation. None of these NaV1.7 mutation carrier groups had evidence of an increased risk of chronic or neuropathic pain. Similarly, no evidence of an increase in prescriptions for opioid analgesics or anti-neuropathic pain medications was found. Subsequent pathogenicity prediction analysis using AlphaMissense, CADD, and EVE indicated that SCN9A variants called in UK Biobank (20/59) were significantly less likely to be rated pathogenic than those that were absent from the cohort (39/59). These findings show that almost one third of the previously reported pathogenic SCN9A gain-of-function variants are likely to be benign from a pain perspective. This study challenges the previously assumed high penetrance of these SCN9A gain-of-function variants for chronic pain and we make recommendations to optimise the evidence-based criteria for genetic association studies investigating the role of ion channel variants in the pathogenesis of pain. Competing Interest Statement GWTN was funded by a BBSRC CASE studentship with Eli Lilly & Company. GWTN has received consultancy fees from Grunenthal GmbH within the last 2 years. APN, KGP, and AK are current or former employees of Eli Lilly and Company and may own stock in this company. KGP is a current or former employee of Grunenthal GmbH. AEP has undertaken consultancy work for Lateral Pharma and has a research grant from Eli Lilly & Company on an unrelated topic. Funding Statement GWTN was funded by a BBSRC CASE industrial collaboration doctoral training studentship award with Eli Lilly & Company. Author Declarations 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: This research has been conducted using data from UK Biobank, a major biomedical database under project ID 64765. The UK Biobank database received ethical approval from the North-West Haydock Research Ethics Committee (REC reference 21/NW/0157) and participants gave informed consent. 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 Data Availability The code to reproduce this analysis is available at https://github.com/graemenewton/Newton_2025_NaV_UKB