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 Degenhardt; Marek 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

doi:10.1136/gutjnl-2020-323868

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 journal › Article › peer-review

Abstract

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 language	English (US)
Pages (from-to)	1538-1549
Number of pages	12
Journal	Gut
Volume	70
Issue number	8
DOIs	https://doi.org/10.1136/gutjnl-2020-323868
State	Published - Aug 1 2021

Keywords

anal canal histopathology
anorectal disorders
genetics

ASJC Scopus subject areas

Gastroenterology

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10.1136/gutjnl-2020-323868

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Zheng, T., Ellinghaus, D., Juzenas, S., Cossais, F., Burmeister, G., Mayr, G., Jørgensen, I. F., Teder-Laving, M., Skogholt, A. H., Chen, S., Strege, P. R., Ito, G., Banasik, K., Becker, T., Bokelmann, F., Brunak, S., Buch, S., Clausnitzer, H., Datz, C., ... Franke, A. (2021). Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease. Gut, 70(8), 1538-1549. https://doi.org/10.1136/gutjnl-2020-323868

Zheng, T, Ellinghaus, D, Juzenas, S, Cossais, F, Burmeister, G, Mayr, G, Jørgensen, IF, Teder-Laving, M, Skogholt, AH, Chen, S, Strege, PR, Ito, G, Banasik, K, Becker, T, Bokelmann, F, Brunak, S, Buch, S, Clausnitzer, H, Datz, C, Degenhardt, F, Doniec, M, Erikstrup, C, Esko, T, Forster, M, Frey, N, Fritsche, LG, Gabrielsen, ME, Gräßle, T, Gsur, A, Gross, J, Hampe, J, Hendricks, A, Hinz, S, Hveem, K, Jongen, J, Junker, R, Karlsen, TH, Hemmrich-Stanisak, G, Kruis, W, Kupcinskas, J, Laubert, T, Rosenstiel, PC, Röcken, C, Laudes, M, Leendertz, FH, Lieb, W, Limperger, V, Margetis, N, Mätz-Rensing, K, Németh, CG, Ness-Jensen, E, Nowak-Göttl, U, Pandit, A, Pedersen, OB, Peleikis, HG, Peuker, K, Rodriguez, CL, Rühlemann, MC, Schniewind, B, Schulzky, M, Skieceviciene, J, Tepel, J, Thomas, L, Uellendahl-Werth, F, Ullum, H, Vogel, I, Volzke, H, Von Fersen, L, Von Schönfels, W, Vanderwerff, B, Wilking, J, Wittig, M, Zeissig, S, Zobel, M, Zawistowski, M, Vacic, V, Sazonova, O, Noblin, ES, Farrugia, G , Beyder, A, Wedel, T, Kahlke, V, Schafmayer, C, D'Amato, M & Franke, A 2021, 'Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease', Gut, vol. 70, no. 8, pp. 1538-1549. https://doi.org/10.1136/gutjnl-2020-323868

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abstract = "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.",

keywords = "anal canal histopathology, anorectal disorders, genetics",

author = "Tenghao Zheng and David Ellinghaus and Simonas Juzenas and Fran{\c c}ois Cossais and Greta Burmeister and Gabriele Mayr and J{\o}rgensen, {Isabella Friis} and Maris Teder-Laving and Skogholt, {Anne Heidi} and Sisi Chen and Strege, {Peter R.} and Go Ito and Karina Banasik and Thomas Becker and Frank Bokelmann and S{\o}ren Brunak and Stephan Buch and Hartmut Clausnitzer and Christian Datz and Frauke Degenhardt and Marek Doniec and Christian Erikstrup and T{\~o}nu Esko and Michael Forster and Norbert Frey and Fritsche, {Lars G.} and Gabrielsen, {Maiken Elvestad} and Tobias Gr{\"a}{\ss}le and Andrea Gsur and Justus Gross and Jochen Hampe and Alexander Hendricks and Sebastian Hinz and Kristian Hveem and Johannes Jongen and Ralf Junker and Karlsen, {Tom Hemming} and Georg Hemmrich-Stanisak and Wolfgang Kruis and Juozas Kupcinskas and Tilman Laubert and Rosenstiel, {Philip C.} and Christoph R{\"o}cken and Matthias Laudes and Leendertz, {Fabian H.} and Wolfgang Lieb and Verena Limperger and Nikolaos Margetis and Kerstin M{\"a}tz-Rensing and N{\'e}meth, {Christopher Georg} and Eivind Ness-Jensen and Ulrike Nowak-G{\"o}ttl and Anita Pandit and Pedersen, {Ole Birger} and Peleikis, {Hans G{\"u}nter} and Kenneth Peuker and Rodriguez, {Cristina Leal} and R{\"u}hlemann, {Malte Christoph} and Bodo Schniewind and Martin Schulzky and Jurgita Skieceviciene and J{\"u}rgen Tepel and Laurent Thomas and Florian Uellendahl-Werth and Henrik Ullum and Ilka Vogel and Henry Volzke and {Von Fersen}, Lorenzo and {Von Sch{\"o}nfels}, Witigo and Brett Vanderwerff and Julia Wilking and Michael Wittig and Sebastian Zeissig and Myrko Zobel and Matthew Zawistowski and Vladimir Vacic and Olga Sazonova and Noblin, {Elizabeth S.} and Gianrico Farrugia and Arthur Beyder and Thilo Wedel and Volker Kahlke and Clemens Schafmayer and Mauro D'Amato and Andre Franke",

note = "Publisher Copyright: {\textcopyright} ",

year = "2021",

month = aug,

day = "1",

doi = "10.1136/gutjnl-2020-323868",

language = "English (US)",

volume = "70",

pages = "1538--1549",

journal = "Gut",

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TY - JOUR

T1 - 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, 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 - Németh, Christopher Georg

AU - Ness-Jensen, Eivind

AU - Nowak-Göttl, Ulrike

AU - Pandit, Anita

AU - Pedersen, Ole Birger

AU - Peleikis, Hans Günter

AU - Peuker, Kenneth

AU - Rodriguez, Cristina Leal

AU - Rühlemann, Malte Christoph

AU - Schniewind, Bodo

AU - Schulzky, Martin

AU - Skieceviciene, Jurgita

AU - Tepel, Jürgen

AU - Thomas, Laurent

AU - Uellendahl-Werth, Florian

AU - Ullum, Henrik

AU - Vogel, Ilka

AU - Volzke, Henry

AU - Von Fersen, Lorenzo

AU - Von Schönfels, Witigo

AU - Vanderwerff, Brett

AU - Wilking, Julia

AU - Wittig, Michael

AU - Zeissig, Sebastian

AU - Zobel, Myrko

AU - Zawistowski, Matthew

AU - Vacic, Vladimir

AU - Sazonova, Olga

AU - Noblin, Elizabeth S.

AU - Farrugia, Gianrico

AU - Beyder, Arthur

AU - Wedel, Thilo

AU - Kahlke, Volker

AU - Schafmayer, Clemens

AU - D'Amato, Mauro

AU - Franke, Andre

PY - 2021/8/1

Y1 - 2021/8/1

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 - anal canal histopathology

KW - anorectal disorders

KW - genetics

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UR - http://www.scopus.com/inward/citedby.url?scp=85105306951&partnerID=8YFLogxK

U2 - 10.1136/gutjnl-2020-323868

DO - 10.1136/gutjnl-2020-323868

M3 - Article

C2 - 33888516

AN - SCOPUS:85105306951

SN - 0017-5749

VL - 70

SP - 1538

EP - 1549

JO - Gut

JF - Gut

IS - 8

ER -

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

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