{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T17:05:38Z","timestamp":1783962338098,"version":"3.55.0"},"posted":{"date-parts":[[2025,3,28]]},"group-title":"Genetic and Genomic Medicine","reference-count":55,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T00:00:00Z","timestamp":1743120000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Please see manuscript for complete funding details"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background and aims<\/jats:title>\n                  <jats:p>Diverticular disease is a common and morbid complex phenotype influenced by both genetic and environmental risk factors. The aim of the current study is to elucidate the genetic architecture of diverticular disease and to corroborate those results with tissue-based analysis.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We performed the largest genome-wide association study (GWAS) meta-analysis for diverticular disease. We employed multiple downstream analytic strategies, including tissue and pathway enrichment, statistical fine-mapping, protein quantitative trait loci, drug-target investigations, and linkage disequilibrium score regression to prioritize causal genes. We utilized single-cell RNA sequencing data and quantitative analysis of surgically resected colon specimens to corroborate our computational biology results.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Our GWAS meta-analysis included 1.3 million individuals across three cohorts and identified 565 independent signals (257 novel) associated with diverticular disease. These were mapped to 432 unique genes. Several lines of evidence linked these genes to alterations in connective tissue biology and colonic motility. Analysis of single-cell RNA sequencing data revealed that prioritized diverticular disease-associated genes are enriched for expression in colonic smooth muscle, fibroblasts, and interstitial cells of Cajal. Quantitative analysis of surgically resected colon specimens found a substantial (43%) reduction in the density of elastin present in the sigmoid colon among those with severe diverticulitis relative to those with diverticulosis.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Diverticular disease is predominantly a disorder of connective tissue biology and colonic motility. Specifically, decreased density of elastin in the muscularis propria may predispose not to diverticulosis but to diverticulitis itself.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.03.27.25324777","type":"posted-content","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T21:05:20Z","timestamp":1743195920000},"source":"Crossref","is-referenced-by-count":2,"title":["Diverticular disease genome-wide association meta-analysis identifies 257 novel loci, implicates structure and motility"],"prefix":"10.64898","author":[{"given":"Christopher J.","family":"Neylan","sequence":"first","affiliation":[{"name":"Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9937-9932","authenticated-orcid":false,"given":"Michael G.","family":"Levin","sequence":"additional","affiliation":[{"name":"Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Corporal Michael Crescenz VA Medical Center, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrielle","family":"Shakt","sequence":"additional","affiliation":[{"name":"Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Beigel","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Health Informatics (DBHi), Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Khodursky","sequence":"additional","affiliation":[{"name":"Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Abramowitz","sequence":"additional","affiliation":[{"name":"Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"The Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell, Hempstead, NY 11549"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma E.","family":"Furth","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert O.","family":"Heuckeroth","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition, Children\u2019s Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104"},{"name":"The Children\u2019s Hospital of Philadelphia Research Institute and Abramson Research Center, 3615 Civic Center Blvd, Philadelphia, PA 19104, USA"},{"name":"Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8009-1632","authenticated-orcid":false,"given":"Scott M.","family":"Damrauer","sequence":"additional","affiliation":[{"name":"Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Corporal Michael 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