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Genome-wide analysis of 944,133 individuals provides insights into the etiology of hemorrhoidal disease

By Tenghao Zheng, David Ellinghaus, Simonas Juzenas, François Cossais, Greta Burmeister, Gabriele Mayr, Isabella Friis Jørgensen, Maris Teder-Laving, Anne Heidi Skogholt, Karina Banasik, Thomas Becker, Frank Bokelmann, Soeren Brunak, Stephan Buch, Hartmut Clausnitzer, Christian Datz, DBDS Consortium, Frauke Degenhardt, Marek Doniec, Christian Erikstrup, tonu esko, Michael Forster, Norbert Frey, Lars G Fritsche, Maiken Elvestad Gabrielsen, Tobias Gräßle, Andrea Gsur, Justus Gross, Jochen Hampe, Alexander Hendricks, Sebastian Hinz, Kristian Hveem, Johannes Jongen, Ralf Junker, Tom Hemming Karlsen, Georg Hemmrich-Stanisak, Wolfgang Kruis, Juozas Kupcinskas, Tilman Laubert, Matthias Laudes, Fabian H Leendertz, Wolfgang Lieb, Verena Limperger, Nikolaos Margetis, Kerstin Mätz-Rensing, Christopher Georg Németh, Eivind Ness-Jensen, Ulrike Nowak-Göttl, Anita Pandit, Ole Birger Pedersen, Hans Günter Peleikis, Kenneth Peuker, Cristina Rodriguez, Malte Rühlemann, Bodo Schniewind, Martin Schulzky, Jurgita Skieceviciene, Jürgen Tepel, Laurent Thomas, Florian Uellendahl-Werth, Henrik Ullum, Ilka Vogel, Henry Völzke, Lorenzo von Fersen, Witigo von Schoenfels, Brett Vanderwerff, Julia Wilking, Michael Wittig, Sebastian Zeissig, Myrko Zobel, Matthew Zawistowski, Vladimir Vacic, Olga Sazonova, Elizabeth S Noblin, The 23andMe Research Team, Thilo Wedel, Volker Kahlke, Clemens Schafmayer, Mauro D'Amato, Andre Franke

Posted 04 Dec 2020
medRxiv DOI: 10.1101/2020.12.03.20242776

Hemorrhoidal disease (HEM) affects a large fraction of the population but its etiology including suspected genetic predisposition is poorly understood. We conducted a GWAS meta-analysis of 218,920 HEM patients and 725,213 controls of European ancestry, demonstrating modest heritability and genetic correlation with several other diseases from the gastrointestinal, neuroaffective and cardiovascular domains. HEM polygenic risk scores validated in 180,435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harboring genes whose expression is enriched in blood vessels and gastrointestinal tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses of affected tissue from HEM patients highlighted HEM gene co-expression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organization of the extracellular matrix. We conclude HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.

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