Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms
| Autor: | Mauro D'Amato, Robert Grützmann, Ilka Vogel, Andreas Walther-Berends, Thomas Becker, Frank Lammert, Michael Schroeder, Petr Sergeev, Laura Sophie Noack, Jürgen Tepel, Jonas Rosendahl, A Herrmann, Thilo Wedel, Clemens Schafmayer, Witigo von Schönfels, Patrick Michl, Wolfgang Kruis, Michael Krawczak, Bodo Schniewind, Holger Hinrichsen, Gerd Focke, Hans Wolfgang Schimming, Ursula Huber-Schönauer, Christina Lange, Sebastian Wolff, Thorsten Jacobi, RV Thangapandi, James W. Harrison, Robin N Beaumont, Philipp Hofer, Martina Böttner, Juozas Kupcinskas, Henry Völzke, Melanie Langheinrich, Christian Datz, Hans Boedeker, Jens Uwe Erk, Mario Brosch, Jessica Tyrrell, Andreas Volk, Andre Franke, Torsten Kucharzik, Leonora Pietsch, Andrew R. Wood, Greta Burmeister, Stephan Buch, Alexander Hendricks, Wolfgang Lieb, Limas Kupčinskas, Juergen Weitz, Michael N. Weedon, François Cossais, Jochen Hampe, Andrea Gsur, Myrko Zobel, Peter T. Schmidt, Stefan Palm, Matthias C. Reichert, Sebastian Hinz, Sebastian Zeissig, Anna Andreasson, Stefanie Brezina, Gernot Leeb |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male medicine.medical_specialty Pathology diverticular disease Perforation (oil well) Neuromuscular Junction Connective tissue Genome-wide association study Epithelium Colonic Diseases Databases Genetic Genotype medicine Humans Genetic Predisposition to Disease genetics Aged Diverticular Diseases business.industry Gastroenterology Middle Aged Diverticulitis medicine.disease United Kingdom Diverticulosis medicine.anatomical_structure Connective Tissue Case-Control Studies Commentary Diverticular disease Medical genetics Female business Genome-Wide Association Study |
| Zdroj: | Gut |
| ISSN: | 1468-3288 0017-5749 |
| Popis: | ObjectiveDiverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease.DesignDiscovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry.ResultsWe discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (pCTAGE1 with a p value of 2.3×10−10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33).ConclusionIn silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction. |
| Databáze: | OpenAIRE |
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