TY - JOUR
T1 - Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease
AU - DBDS Consortium
AU - Zheng, Tenghao
AU - Ellinghaus, David
AU - Juzenas, Simonas
AU - Cossais, François
AU - Burmeister, Greta
AU - Mayr, Gabriele
AU - Jørgensen, Isabella Friis
AU - Teder-Laving, Maris
AU - Skogholt, Anne Heidi
AU - Chen, Sisi
AU - Strege, Peter R
AU - Ito, Go
AU - Banasik, Karina
AU - Becker, Thomas
AU - Bokelmann, Frank
AU - Brunak, Søren
AU - Buch, Stephan
AU - Clausnitzer, Hartmut
AU - Datz, Christian
AU - Degenhardt, Frauke
AU - Doniec, Marek
AU - Erikstrup, Christian
AU - Esko, Tõnu
AU - Forster, Michael
AU - Frey, Norbert
AU - Fritsche, Lars G
AU - Gabrielsen, Maiken Elvestad
AU - Gräßle, Tobias
AU - Gsur, Andrea
AU - Gross, Justus
AU - Hampe, Jochen
AU - Hendricks, Alexander
AU - Hinz, Sebastian
AU - Hveem, Kristian
AU - Jongen, Johannes
AU - Junker, Ralf
AU - Karlsen, Tom Hemming
AU - Hemmrich-Stanisak, Georg
AU - Kruis, Wolfgang
AU - Kupcinskas, Juozas
AU - Laubert, Tilman
AU - Rosenstiel, Philip C
AU - Röcken, Christoph
AU - Laudes, Matthias
AU - Leendertz, Fabian H
AU - Lieb, Wolfgang
AU - Limperger, Verena
AU - Margetis, Nikolaos
AU - Mätz-Rensing, Kerstin
AU - Pedersen, Ole Birger
AU - D'Amato, Mauro
N1 - © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
KW - anorectal disorders
KW - genetics
KW - anal canal histopathology
U2 - 10.1136/gutjnl-2020-323868
DO - 10.1136/gutjnl-2020-323868
M3 - Article
C2 - 33888516
SN - 0017-5749
VL - 70
SP - 1538
EP - 1549
JO - Gut
JF - Gut
IS - 8
ER -