{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T10:46:46Z","timestamp":1792579606338,"version":"4.5.0"},"reference-count":86,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":279,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Biotechnology and Biological Sciences Research Council Cooperative Awards in Science and Engineering"},{"DOI":"10.13039\/100004312","name":"Eli Lilly & Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004312","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The voltage-gated sodium channels NaV1.7, NaV1.8 and NaV1.9, encoded by the SCN9A, SCN10A and SCN11A genes, respectively, are integral to nociceptor excitability and pain sensation. Multiple gain-of-function mutations in these ion channels have been reported to cause autosomal dominant painful channelopathies, including primary erythromelalgia, paroxysmal extreme pain disorder and familial episodic pain. Conversely, autosomal recessive loss-of-function mutations in NaV1.7 have been reported to cause painless channelopathies. The prevalence and impact on carriers of these voltage-gated sodium channel genetic variants in the wider population has yet to be explored. A combined genetic database and literature search was performed to identify pathogenic gain-of-function variants linked to painful channelopathies which had supporting in vitro electrophysiological evidence. Loss-of-function variants were identified by their inferred impact upon protein sequence. We investigated these variants within the UK Biobank cohort 500k whole-exome sequencing dataset. Logistic regression was used to examine whether carrying these variants was associated with chronic pain, neuropathic pain, and analgesic or anti-neuropathic drug prescriptions (adjusting for age, sex and 10 genetic principal components). For NaV1.7, 20\/59 putative pathogenic gain-of-function mutations identified from literature were found in UK Biobank, with 148 901 carriers (&amp;gt;29% of the cohort). For NaV1.8, 4\/5 gain-of-function mutations were found, with 1104 carriers. For NaV1.9, 13\/17 gain-of-function mutations were found, with 1324 carriers. For predicted loss-of-function mutations in NaV1.7, NaV1.8 and NaV1.9, there were 723, 1307 and 1143 heterozygous carriers, respectively, and 2 homozygous NaV1.9 loss-of-function carriers. A total of 21 NaV mutation groups had \u226550 heterozygous carriers allowing logistic regression analysis. None of these groups had a significantly altered risk of chronic or neuropathic pain. Similarly, no differences in prescriptions of opioid analgesics or anti-neuropathic pain medications were found. Subsequent pathogenicity prediction indicated that the gain-of-function variants called in UK Biobank had significantly lower predicted pathogenicity scores than those that were absent from the cohort. These findings show that over one-third of the previously reported pathogenic NaV1.7 gain-of-function mutations are likely to be benign for pain. This study challenges the previously assumed high penetrance of these NaV gain-of-function mutations for chronic pain, and we make recommendations to optimize the evidence-based criteria for genetic association studies investigating the role of ion channel variants in the pathogenesis of pain.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag374","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:37:00Z","timestamp":1791286620000},"source":"Crossref","is-referenced-by-count":0,"title":["NaV1.7, 1.8 and 1.9 mutations linked to painful channelopathies have no pain phenotype in UK Biobank"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4924-0112","authenticated-orcid":false,"given":"Graeme W T","family":"Newton","sequence":"first","affiliation":[{"name":"Anaesthesia, Pain, and Critical Care Sciences, School of Physiology, Pharmacology, & Neuroscience, University of Bristol , Bristol BS8 1TD ,","place":["UK"]},{"name":"Newton Research , Kirkwall KW15 1JQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corin","family":"Charman","sequence":"additional","affiliation":[{"name":"Anaesthesia, Pain, and Critical Care Sciences, School of Physiology, Pharmacology, & Neuroscience, University of Bristol , Bristol BS8 1TD ,","place":["UK"]},{"name":"Eli Lilly & Company , Bracknell RG12 1PU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aidan P","family":"Nickerson","sequence":"additional","affiliation":[{"name":"Anaesthesia, Pain, and Critical Care Sciences, School of Physiology, Pharmacology, & Neuroscience, University of Bristol , Bristol BS8 1TD ,","place":["UK"]},{"name":"Eli Lilly & Company , Bracknell RG12 1PU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith G","family":"Phillips","sequence":"additional","affiliation":[{"name":"Anaesthesia, Pain, and Critical Care Sciences, School of Physiology, Pharmacology, & Neuroscience, University of Bristol , Bristol BS8 1TD ,","place":["UK"]},{"name":"Gr\u00fcnenthal GmbH , Aachen 502099 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achim","family":"Kless","sequence":"additional","affiliation":[{"name":"Eli Lilly & Company , Bracknell RG12 1PU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James P","family":"Dunham","sequence":"additional","affiliation":[{"name":"Anaesthesia, Pain, and Critical Care Sciences, School of Physiology, Pharmacology, & Neuroscience, University of Bristol , Bristol BS8 1TD ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony E","family":"Pickering","sequence":"additional","affiliation":[{"name":"Anaesthesia, Pain, and Critical Care Sciences, School of Physiology, Pharmacology, & Neuroscience, University of Bristol , Bristol BS8 1TD 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