{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T21:49:09Z","timestamp":1793742549898,"version":"4.6.1"},"posted":{"date-parts":[[2026,4,15]]},"group-title":"Genetic and Genomic Medicine","reference-count":65,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest human cancers. The current largest published PDAC Genome-Wide Association Study (GWAS) identified 23 genetic risk signals, but most lack sufficient characterization. This study aimed to functionally characterize the chr13q12.2 (\n                  <jats:italic>PLUT<\/jats:italic>\n                  \/\n                  <jats:italic>PDX1<\/jats:italic>\n                  ) PDAC GWAS risk locus. Fine-mapping, luciferase reporter assays, and electrophoretic mobility shift assays implicated rs9581943, a\n                  <jats:italic>PDX1<\/jats:italic>\n                  promoter SNP, as a functional variant underlying this GWAS signal. GTEx expression QTL analyses identified rs9581943 as a significant\n                  <jats:italic>PDX1<\/jats:italic>\n                  eQTL in pancreas, and CRISPR\/Cas9 editing in PDAC-derived cell lines confirmed a functional relationship. PDX1 is a transcription factor involved in early pancreas development and \u03b2-cell homeostasis, but its role in exocrine pancreatic cells is unclear. Single-nucleus RNA-seq analyses of pancreatic acinar and ductal cells from neonatal, adult, and chronic pancreatitis donors suggested PDX1 activity alleviates high secretory load and ER-stress in acinar and biases ducts toward homeostatic phenotypes. Similarly, scRNA-seq analyses of pancreatic tumors suggested PDX1 activity reduces biosynthetic and inflammatory stress and promotes epithelial differentiation. Our study therefore implicates rs9581943 as a causal variant for the chr13q12.2 PDAC GWAS signal wherein the risk allele reduces\n                  <jats:italic>PDX1<\/jats:italic>\n                  expression, eroding PDX1\u2019s capacity to buffer stress and stabilize epithelial cell fate in the exocrine compartment.\n                <\/jats:p>","DOI":"10.64898\/2026.04.13.26350790","type":"posted-content","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T22:50:15Z","timestamp":1776293415000},"source":"Crossref","is-referenced-by-count":1,"title":["Characterization of a pancreatic cancer GWAS signal suggests PDX1 buffers stress in the exocrine pancreas"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6944-1996","authenticated-orcid":false,"given":"Jason W.","family":"Hoskins","sequence":"first","affiliation":[{"name":"Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor A.","family":"Christensen","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daina","family":"Eiser","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Char","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Mobaraki","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aidan","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Collins","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zhong","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minal B.","family":"Patel","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gauri","family":"Prasad","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America"},{"name":"Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium (PanScan\/PanC4)","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. 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