TY - JOUR
TI - Genome-wide analysis of 944 133 individuals provides insights into the
etiology of haemorrhoidal disease
AU - Zheng, Tenghao
AU - Ellinghaus, David
AU - Juzenas, Simonas
AU - Cossais,
AU - Francois
AU - Burmeister, Greta
AU - Mayr, Gabriele
AU - Jorgensen,
AU - Isabella Friis
AU - Teder-Laving, Maris
AU - Skogholt, Anne Heidi and
AU - Chen, Sisi
AU - Strege, Peter R.
AU - Ito, Go
AU - Banasik, Karina and
AU - Becker, Thomas
AU - Bokelmann, Frank
AU - Brunak, Soren
AU - Buch, Stephan
AU - and Clausnitzer, Hartmut
AU - Datz, Christian
AU - Degenhardt, Frauke and
AU - Doniec, Marek
AU - Erikstrup, Christian
AU - Esko, Tonu
AU - Forster,
AU - Michael
AU - Frey, Norbert
AU - Fritsche, Lars G.
AU - Gabrielsen, Maiken
AU - Elvestad
AU - Grassle, Tobias
AU - Gsur, Andrea
AU - Gross, Justus and
AU - Hampe, Jochen
AU - Hendricks, Alexander
AU - Hinz, Sebastian
AU - Hveem,
AU - Kristian
AU - Jongen, Johannes
AU - Junker, Ralf
AU - Karlsen, Tom Hemming
AU - and Hemmrich-Stanisak, Georg
AU - Kruis, Wolfgang
AU - Kupcinskas, Juozas
AU - and Laubert, Tilman
AU - Rosenstiel, Philip C.
AU - Roecken, Christoph and
AU - Laudes, Matthias
AU - Leendertz, Fabian H.
AU - Lieb, Wolfgang and
AU - Limperger, Verena
AU - Margetis, Nikolaos
AU - Matz-Rensing, Kerstin and
AU - Nemeth, Christopher Georg
AU - Ness-Jensen, Eivind
AU - Nowak-Gottl,
AU - Ulrike
AU - Pandit, Anita
AU - Pedersen, Ole Birger
AU - Peleikis, Hans
AU - Gunter
AU - Peuker, Kenneth
AU - Rodriguez, Cristina Leal
AU - Ruehlemann,
AU - Malte Christoph
AU - Schniewind, Bodo
AU - Schulzky, Martin and
AU - Skieceviciene, Jurgita
AU - Tepel, Jurgen
AU - Thomas, Laurent and
AU - Uellendahl-Werth, Florian
AU - Ullum, Henrik
AU - Vogel, Ilka
AU - Volzke,
AU - Henry
AU - von Fersen, Lorenzo
AU - von Schonfels, Witigo
AU - Vanderwerff,
AU - Brett
AU - Wilking, Julia
AU - Wittig, Michael
AU - Zeissig, Sebastian and
AU - Zobel, Myrko
AU - Zawistowski, Matthew
AU - Vacic, Vladimir
AU - Sazonova,
AU - Olga
AU - Noblin, Elizabeth S.
AU - Farrugia, Gianrico
AU - Beyder, Arthur
AU - and Wedel, Thilo
AU - Kahlke, Volker
AU - Schafmayer, Clemens
AU - D'Amato,
AU - Mauro
AU - Franke, Andre
AU - DBDS Consortium
AU - The 23andMe Res Team
JO - Gut Pathogens
PY - 2021
VL - 70
TODO - 8
SP - 1538-1549
PB - BMJ Publishing Group
SN - 1757-4749
TODO - 10.1136/gutjnl-2020-323868
TODO - anorectal disorders; genetics; anal canal histopathology
TODO - 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.
ER -