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

Tenghao Zheng, David Ellinghaus, Simonas Juzenas, François Cossais, Greta Burmeister, Gabriele Mayr, Isabella Friis Jørgensen, Maris Teder-Laving, Anne Heidi Skogholt, Sisi Chen, Peter R. Strege, Go Ito, Karina Banasik, Thomas Becker, Frank Bokelmann, Søren Brunak, Stephan Buch, Hartmut Clausnitzer, Christian Datz, Frauke DegenhardtMarek Doniec, Christian Erikstrup, Tõnu 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, Philip C. Rosenstiel, Christoph Röcken, 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 Leal Rodriguez, Malte Christoph Rühlemann, Bodo Schniewind, Martin Schulzky, Jurgita Skieceviciene, Jürgen Tepel, Laurent Thomas, Florian Uellendahl-Werth, Henrik Ullum, Ilka Vogel, Henry Volzke, Lorenzo Von Fersen, Witigo Von Schönfels, Brett Vanderwerff, Julia Wilking, Michael Wittig, Sebastian Zeissig, Myrko Zobel, Matthew Zawistowski, Vladimir Vacic, Olga Sazonova, Elizabeth S. Noblin, Gianrico Farrugia, Arthur Beyder, Thilo Wedel, Volker Kahlke, Clemens Schafmayer, Mauro D'Amato, Andre Franke

Research output: Contribution to journalArticlepeer-review


Objective Haemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date. Design We conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry. Results We demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS 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 harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix. Conclusion HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.

Original languageEnglish (US)
Pages (from-to)1538-1549
Number of pages12
Issue number8
StatePublished - Aug 1 2021


  • anal canal histopathology
  • anorectal disorders
  • genetics

ASJC Scopus subject areas

  • Gastroenterology


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