Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease
Authors: Zheng Tenghao , Ellinghaus David , Juzenas Simonas , Cossais François , Burmeister Greta , Mayr Gabriele , Jørgensen Isabella Friis , Teder-Laving Maris , Skogholt Anne Heidi , Chen Sisi , Strege Peter R , Ito Go , Banasik Karina , Becker Thomas , Bokelmann Frank , Brunak Søren , Buch Stephan , Clausnitzer Hartmut , Datz Christian ,   DBDS Consortium, Degenhardt Frauke , Doniec Marek , Erikstrup Christian , Esko Tõnu , Forster Michael , Frey Norbert , Fritsche Lars G , Gabrielsen Maiken Elvestad , Gräßle Tobias , Gsur Andrea , Gross Justus , Hampe Jochen , Hendricks Alexander , Hinz Sebastian , Hveem Kristian , Jongen Johannes , Junker Ralf , Karlsen Tom Hemming , Hemmrich-Stanisak Georg , Kruis Wolfgang , Kupcinskas Juozas , Laubert Tilman , Rosenstiel Philip C , Röcken Christoph , Laudes Matthias , Leendertz Fabian H , Lieb Wolfgang , Limperger Verena , Margetis Nikolaos , Mätz-Rensing Kerstin , Németh Christopher Georg , Ness-Jensen Eivind , Nowak-Göttl Ulrike , Pandit Anita , Pedersen Ole Birger , Peleikis Hans Günter , Peuker Kenneth , Rodriguez Cristina Leal , Rühlemann Malte Christoph , Schniewind Bodo , Schulzky Martin , Skieceviciene Jurgita , Tepel Jürgen , Thomas Laurent , Uellendahl-Werth Florian , Ullum Henrik , Vogel Ilka , Volzke Henry , von Fersen Lorenzo , von Schönfels Witigo , Vanderwerff Brett , Wilking Julia , Wittig Michael , Zeissig Sebastian , Zobel Myrko , Zawistowski Matthew , Vacic Vladimir , Sazonova Olga , Noblin Elizabeth S ,   The 23andMe Research Team, Farrugia Gianrico , Beyder Arthur , Wedel Thilo , Kahlke Volker , Schafmayer Clemens , D'Amato Mauro , Franke Andre 
Published: April 2021

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.