Περίληψη:
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.
Συγγραφείς:
Zheng, Tenghao
Ellinghaus, David
Juzenas, Simonas
Cossais,
Francois
Burmeister, Greta
Mayr, Gabriele
Jorgensen,
Isabella Friis
Teder-Laving, Maris
Skogholt, Anne Heidi and
Chen, Sisi
Strege, Peter R.
Ito, Go
Banasik, Karina and
Becker, Thomas
Bokelmann, Frank
Brunak, Soren
Buch, Stephan
and Clausnitzer, Hartmut
Datz, Christian
Degenhardt, Frauke and
Doniec, Marek
Erikstrup, Christian
Esko, Tonu
Forster,
Michael
Frey, Norbert
Fritsche, Lars G.
Gabrielsen, Maiken
Elvestad
Grassle, Tobias
Gsur, Andrea
Gross, Justus and
Hampe, Jochen
Hendricks, Alexander
Hinz, Sebastian
Hveem,
Kristian
Jongen, Johannes
Junker, Ralf
Karlsen, Tom Hemming
and Hemmrich-Stanisak, Georg
Kruis, Wolfgang
Kupcinskas, Juozas
and Laubert, Tilman
Rosenstiel, Philip C.
Roecken, Christoph and
Laudes, Matthias
Leendertz, Fabian H.
Lieb, Wolfgang and
Limperger, Verena
Margetis, Nikolaos
Matz-Rensing, Kerstin and
Nemeth, Christopher Georg
Ness-Jensen, Eivind
Nowak-Gottl,
Ulrike
Pandit, Anita
Pedersen, Ole Birger
Peleikis, Hans
Gunter
Peuker, Kenneth
Rodriguez, Cristina Leal
Ruehlemann,
Malte Christoph
Schniewind, Bodo
Schulzky, Martin and
Skieceviciene, Jurgita
Tepel, Jurgen
Thomas, Laurent and
Uellendahl-Werth, Florian
Ullum, Henrik
Vogel, Ilka
Volzke,
Henry
von Fersen, Lorenzo
von Schonfels, Witigo
Vanderwerff,
Brett
Wilking, Julia
Wittig, Michael
Zeissig, Sebastian and
Zobel, Myrko
Zawistowski, Matthew
Vacic, Vladimir
Sazonova,
Olga
Noblin, Elizabeth S.
Farrugia, Gianrico
Beyder, Arthur
and Wedel, Thilo
Kahlke, Volker
Schafmayer, Clemens
D'Amato,
Mauro
Franke, Andre
DBDS Consortium
The 23andMe Res Team
