{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:44:51Z","timestamp":1786977891658,"version":"build-2736575974"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2021,12,10]],"date-time":"2021-12-10T00:00:00Z","timestamp":1639094400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>Genome\u2010wide association studies (GWAS) have identified several risk loci for gallstone disease. As with most polygenic traits, it is likely that many genetic determinants are undiscovered. The aim of this study was to identify genetic variants that represent new targets for gallstone research and treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results<\/jats:title>\n                    <jats:p>\n                      We performed a GWAS of 28,627 gallstone cases and 348,373 controls in the UK Biobank, replicated findings in a Scottish cohort (1089 cases, 5228 controls), and conducted a GWA meta\u2010analysis (43,639 cases, 506,798 controls) with the FinnGen cohort. We assessed pathway enrichment using gene\u2010based then gene\u2010set analysis and tissue expression of identified genes in Genotype\u2010Tissue Expression project data. We constructed a polygenic risk score (PRS) and evaluated phenotypic traits associated with the score. Seventy\u2010five risk loci were identified (\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u00a0&lt;\u00a05 \u00d7\u00a010\n                      <jats:sup>\u22128<\/jats:sup>\n                      ), of which 46 were new. Pathway enrichment revealed associations with lipid homeostasis, glucuronidation, phospholipid metabolism, and gastrointestinal motility. Anoctamin 1 (\n                      <jats:italic toggle=\"yes\">ANO1<\/jats:italic>\n                      ) and transmembrane Protein 147 (\n                      <jats:italic toggle=\"yes\">TMEM147<\/jats:italic>\n                      ), both in novel, replicated loci, are expressed in the gallbladder and gastrointestinal tract. Both regulate gastrointestinal motility. The gallstone risk allele rs7599\u2010A leads to suppression of hepatic\n                      <jats:italic toggle=\"yes\">TMEM147<\/jats:italic>\n                      expression, suggesting that the protein protects against gallstone formation. The highest decile of the PRS demonstrated a 6\u2010fold increased odds of gallstones compared with the lowest decile. The PRS was strongly associated with increased body mass index, serum liver enzymes, and C\u2010reactive protein concentrations, and decreased lipoprotein cholesterol concentrations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This GWAS demonstrates the polygenic nature of gallstone risk and identifies 46 novel susceptibility loci. We implicate genes influencing gastrointestinal motility in the pathogenesis of gallstones.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.32199","type":"journal-article","created":{"date-parts":[[2021,10,17]],"date-time":"2021-10-17T15:23:44Z","timestamp":1634484224000},"page":"1081-1094","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":39,"title":["Genome\u2010wide analysis identifies gallstone\u2010susceptibility loci including genes regulating gastrointestinal motility"],"prefix":"10.1097","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7635-1868","authenticated-orcid":false,"given":"Cameron J.","family":"Fairfield","sequence":"first","affiliation":[{"name":"Center for Medical Informatics,Usher Institute,University of Edinburgh,Edinburgh,Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas M.","family":"Drake","sequence":"additional","affiliation":[{"name":"Center for Medical Informatics,Usher Institute,University of Edinburgh,Edinburgh,Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riinu","family":"Pius","sequence":"additional","affiliation":[{"name":"Center for Medical Informatics,Usher Institute,University of Edinburgh,Edinburgh,Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew\u00a0D.","family":"Bretherick","sequence":"additional","affiliation":[{"name":"MRC Human Genetics Unit,Institute of Genetics and Cancer,University of Edinburgh,Edinburgh,Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Archie","family":"Campbell","sequence":"additional","affiliation":[{"name":"Center for Medical Informatics,Usher Institute,University of Edinburgh,Edinburgh,Scotland"},{"name":"Center for Genomic and Experimental Medicine,Institute of Genetics and Cancer,University of Edinburgh,Edinburgh,Scotland"},{"name":"Health Data Research UK,University of Edinburgh,Edinburgh,Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W.","family":"Clark","sequence":"additional","affiliation":[{"name":"Center for Global Health Research,Usher Institute,University of Edinburgh,Edinburgh,Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5741-1471","authenticated-orcid":false,"given":"Jonathan\u00a0A.","family":"Fallowfield","sequence":"additional","affiliation":[{"name":"Centre for Inflammation Research,Queen\u2019s Medical Research Institute,University of Edinburgh,Edinburgh,Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Hayward","sequence":"additional","affiliation":[{"name":"MRC Human Genetics Unit,Institute of Genetics and Cancer,University of Edinburgh,Edinburgh,Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2273-4094","authenticated-orcid":false,"given":"Neil C.","family":"Henderson","sequence":"additional","affiliation":[{"name":"Centre for Inflammation Research,Queen\u2019s Medical Research Institute,University of Edinburgh,Edinburgh,Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrii","family":"Iakovliev","sequence":"additional","affiliation":[{"name":"Center for Population Health Sciences,Usher Institute,University of Edinburgh,Edinburgh,Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter K.","family":"Joshi","sequence":"additional","affiliation":[{"name":"Center for Global Health Research,Usher Institute,University of Edinburgh,Edinburgh,Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas L.","family":"Mills","sequence":"additional","affiliation":[{"name":"Center for Cardiovascular Science,Queen\u2019s Medical Research Institute,University of Edinburgh,Edinburgh,Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Porteous","sequence":"additional","affiliation":[{"name":"Center for Genomic and Experimental Medicine,Institute of Genetics and Cancer,University of Edinburgh,Edinburgh,Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prakash","family":"Ramachandran","sequence":"additional","affiliation":[{"name":"Centre for Inflammation Research,Queen\u2019s Medical Research Institute,University of Edinburgh,Edinburgh,Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert K.","family":"Semple","sequence":"additional","affiliation":[{"name":"Center for Cardiovascular Science,Queen\u2019s Medical Research Institute,University of Edinburgh,Edinburgh,Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine 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