{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T14:53:39Z","timestamp":1791557619661,"version":"4.3.4"},"reference-count":53,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Primary Biliary Cholangitis (PBC) is an autoimmune cholangiopathy with polygenic architecture and unknown aetiology. Evidence links Neanderthal\u2010derived genetic variants to autoimmune conditions; however, their contribution to PBC susceptibility remains unexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>We investigate whether archaic alleles influence PBC risk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>Genotype data from four PBC cohorts were analysed: CANUK (4615 cases, 9233 controls), OLD IT (444 cases, 901 controls), NEW IT (255 cases, 579 controls) and MAYO (891 cases, 621 controls). Association testing with 235\u2009592 Neanderthal Informative Markers (NIMs) was performed, adjusting for population stratification. Heritability was estimated using RHE\u2010mc and temporal haplotype dynamics were assessed using ancient DNA data from Europe and Asia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A Neanderthal\u2010derived variant in\n                      <jats:italic>TNPO3<\/jats:italic>\n                      (rs12531711), previously reported by Cordell et\u00a0al. showed strong association in CANUK (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20092.04\u2009\u00d7\u200910\n                      <jats:sup>\u221226<\/jats:sup>\n                      ) and replicated across all validation cohorts. This variant functions as an eQTL, upregulating\n                      <jats:italic>IRF5<\/jats:italic>\n                      and downregulating\n                      <jats:italic>TNPO3<\/jats:italic>\n                      in blood. It is rare in African populations but common both in Europeans and Asians. Temporal analysis of the haplotype carrying rs12531711 revealed frequency increased substantially during the Bronze Age (5000\u20133000 BP), rising from 2.0% to 7.7% in Europe and 3.4% to 17.4% in Asia, before stabilizing. Despite this strong single\u2010variant association, the heritability explained by NIMs was not significantly different from that of non\u2010NIM variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>A Neanderthal\u2010derived variant contributes to PBC risk and its frequency increased in the Bronze Age, possibly due to pathogen\u2010driven selection. Archaic introgression overall has limited influence on PBC heritability. Functional studies are needed to elucidate the role of rs12531711.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/liv.70868","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T05:08:17Z","timestamp":1790140097000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Genetic Risk Variant Associated With the Risk of Primary Biliary Cholangitis Is Inherited From Neanderthals"],"prefix":"10.1111","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5086-0514","authenticated-orcid":false,"given":"Alessio","family":"Gerussi","sequence":"first","affiliation":[{"name":"Department of Medicine and Surgery University of Milano\u2010Bicocca  Monza Italy"},{"name":"Division of Gastroenterology, Center for Autoimmune Liver Diseases European Reference Network on Hepatological Diseases (ERN RARE\u2010LIVER), Fondazione IRCCS San Gerardo Dei Tintori  Monza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2330-3230","authenticated-orcid":false,"given":"Chiara","family":"Caime","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery University of Milano\u2010Bicocca  Monza Italy"},{"name":"Division of Gastroenterology, Center for Autoimmune Liver Diseases European Reference Network on Hepatological Diseases (ERN RARE\u2010LIVER), Fondazione IRCCS San Gerardo Dei Tintori  Monza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harold","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Computer Science University of California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1879-5572","authenticated-orcid":false,"given":"Heather J.","family":"Cordell","sequence":"additional","affiliation":[{"name":"Population Health Sciences Institute, Faculty of Medical Sciences Newcastle University  UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George F.","family":"Mells","sequence":"additional","affiliation":[{"name":"Population Health Sciences Institute, Faculty of Medical Sciences Newcastle University  UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard N.","family":"Sandford","sequence":"additional","affiliation":[{"name":"Academic Department of Medical Genetics Cambridge University  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0083-5564","authenticated-orcid":false,"given":"David E.","family":"Jones","sequence":"additional","affiliation":[{"name":"Faculty of Medical Sciences Newcastle University  Newcastle UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gideon","family":"Hirschfield","sequence":"additional","affiliation":[{"name":"The Autoimmune and Rare Liver Disease Programme, Division of Gastroenterology and Hepatology Toronto General Hospital  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine A.","family":"Siminovitch","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Toronto  Toronto Ontario Canada"},{"name":"Mount Sinai Hospital, Lunenfeld Tanenbaum Research Institute and Toronto General Research Institute  Toronto Canada"},{"name":"Department of Immunology University of Toronto  Toronto Ontario Canada"},{"name":"Institute of Medical Sciences University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5245-2680","authenticated-orcid":false,"given":"M. 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