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Genome-Wide Analysis of 944 133 Individuals Provides Insights Into Colon Original research Genome- wide analysis of 944 133 individuals Gut: first published as 10.1136/gutjnl-2020-323868 on 22 April 2021. Downloaded from provides insights into the etiology of haemorrhoidal disease Tenghao Zheng ,1,2 David Ellinghaus ,3,4 Simonas Juzenas ,3,5 François Cossais,6 Greta Burmeister,7 Gabriele Mayr,3 Isabella Friis Jørgensen,4 Maris Teder- Laving,8 Anne Heidi Skogholt,9 Sisi Chen,10 Peter R Strege,10 Go Ito,3,11 Karina Banasik,4 Thomas Becker,12 Frank Bokelmann,13 Søren Brunak,4 Stephan Buch,14 Hartmut Clausnitzer,15 Christian Datz ,16 DBDS Consortium, Frauke Degenhardt,3 Marek Doniec,17 Christian Erikstrup,18 Tõnu Esko,8 Michael Forster ,3 Norbert Frey,19,20,21 Lars G Fritsche,22 9 23,24 25 7 ► Additional supplemental Maiken Elvestad Gabrielsen, Tobias Gräßle, Andrea Gsur , Justus Gross, material is published online Jochen Hampe ,14,26 Alexander Hendricks,7 Sebastian Hinz,7 Kristian Hveem,9 only. To view, please visit the 27,28 15 29 journal online (http:// dx. doi. org/ Johannes Jongen, Ralf Junker, Tom Hemming Karlsen, 10. 1136/ gutjnl- 2020- 323868). Georg Hemmrich- Stanisak,3 Wolfgang Kruis,30 Juozas Kupcinskas,31 For numbered affiliations see 27,28,32 3,33 34 end of article. Tilman Laubert, Philip C Rosenstiel, Christoph Röcken , Matthias Laudes,35 Fabian H Leendertz,23,24 Wolfgang Lieb,36 Verena Limperger,15 Correspondence to 37 38 12,39 Prof Mauro D’Amato, Nikolaos Margetis, Kerstin Mätz- Rensing, Christopher Georg Németh, Gastrointestinal Genetics Lab, Eivind Ness- Jensen ,9,40,41 Ulrike Nowak- Göttl,15 Anita Pandit,22 CIC bioGUNE - BRTA, Bizkaia 42 27,28 14,26 Science and Technology Park, Ole Birger Pedersen, Hans Günter Peleikis, Kenneth Peuker, Building 801A, 48160 Derio, 4 3 43 Spain; mdamato@ cicbiogune. es Cristina Leal Rodriguez, Malte Christoph Rühlemann , Bodo Schniewind, and Prof Andre Franke, Institute 3 31 44 9,45,46,47 of Clinical Molecular Biology Martin Schulzky, Jurgita Skieceviciene, Jürgen Tepel, Laurent Thomas, http://gut.bmj.com/ 3 48 49 50 (IKMB) & University Hospital Florian Uellendahl- Werth, Henrik Ullum, Ilka Vogel, Henry Volzke, Schleswig- Holstein (UKSH), 51 12 22 7 Christian- Albrechts- University of Lorenzo von Fersen, Witigo von Schönfels, Brett Vanderwerff, Julia Wilking, Kiel (CAU), Rosalind- Franklin- Str. 3 14,26 52 22 12, D-24105 Kiel, Germany; Michael Wittig, Sebastian Zeissig, Myrko Zobel, Matthew Zawistowski, 53 53 53 a. franke@ mucosa. de Vladimir Vacic, Olga Sazonova, Elizabeth S Noblin, The 23andMe Research Team, 10 10 6 27,28,54 TZ, DE and SJ contributed Gianrico Farrugia , Arthur Beyder, Thilo Wedel, Volker Kahlke, on September 24, 2021 by guest. Protected copyright. equally. 7 1,2,55,56 3,33 CS, MD and AF contributed Clemens Schafmayer, Mauro D’Amato , Andre Franke equally. Received 18 December 2020 Revised 19 March 2021 ABSTRACT Results We demonstrate modest heritability and genetic Accepted 30 March 2021 Objective Haemorrhoidal disease (HEM) affects a large correlation of HEM with several other diseases from the Published Online First 22 April 2021 and silently suffering fraction of the population but its GI, neuroaffective and cardiovascular domains. HEM PRS aetiology, including suspected genetic predisposition, validated in 180 435 individuals from independent datasets is poorly understood. We report the first genome- wide allowed the identification of those at risk and correlated with association study (GWAS) meta- analysis to identify younger age of onset and recurrent surgery. We identified genetic risk factors for HEM to date. ► http:// dx. doi. org/ 10.1136/ 102 independent HEM risk loci harbouring genes whose Design We conducted a GWAS meta- analysis of 218 gutjnl- 2021- 324817 expression is enriched in blood vessels and GI tissues, and 920 patients with HEM and 725 213 controls of European in pathways associated with smooth muscles, epithelial ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and and endothelial development and morphogenesis. Network © Author(s) (or their other traits as well as calculated HEM polygenic risk transcriptomic analyses highlighted HEM gene coexpression employer(s)) 2021. Re- use modules that are relevant to the development and integrity permitted under CC BY-NC . No scores (PRS) and evaluated their translational potential commercial re-use . See rights in independent datasets. Using functional annotation of the musculoskeletal and epidermal systems, and the and permissions. Published of GWAS results, we identified HEM candidate genes, organisation of the extracellular matrix. by BMJ. which differential expression and coexpression in HEM Conclusion HEM has a genetic component that To cite: Zheng T, tissues were evaluated employing RNA- seq analyses. The predisposes to smooth muscle, epithelial and connective Ellinghaus D, Juzenas S, et al. localisation of expressed proteins at selected loci was tissue dysfunction. Gut 2021;70:1538–1549. investigated by immunohistochemistry. 1538 Zheng T, et al. Gut 2021;70:1538–1549. doi:10.1136/gutjnl-2020-323868 Colon related to the large number of haemorrhoidectomies performed Significance of this study every year.4 A number of HEM risk factors have been suggested, including Gut: first published as 10.1136/gutjnl-2020-323868 on 22 April 2021. Downloaded from What is already known about this subject? human erect position. The tight anal sealing provided by the ► Human haemorrhoidal disease (HEM) is a prevalent anorectal elaborated haemorrhoidal plexus may have developed during pathology characterised by the symptomatic enlargement human evolution co- occurring with permanent bipedalism, as and distal displacement of anal cushions. shown by our histology comparison of four different mammals ► As a consequence of scarce research and of being a taboo (human, gorilla, baboon, mouse; online supplemental figure 1, topic in society, only a few HEM non- genetic risk factors online supplemental material 1). Other suggested risk factors have been suggested, thus the aetiology of the disease still are a sedentary lifestyle, obesity, reduced dietary fibre intake, remains unclear. spending excess time on the toilet, straining during defeca- ► Genetic susceptibility to HEM has been suspected but was tion, strenuous lifting, constipation, diarrhoea, pelvic floor never systematically investigated. dysfunction, pregnancy and giving natural birth, with several What are the new findings? being controversially reported. The hypothetical model shown in online supplemental figure 2 summarises the contemporary ► Here, we report the first well- powered genome- wide 5 association study (GWAS) meta- analysis with a sample size concepts regarding the pathophysiology of HEM development. of 944 133 individuals to identify genetic risk factors for HEM. Until today, HEM aetiopathogenesis is poorly investigated, and ► We describe 102 novel independent HEM risk loci that are neither the exact molecular mechanisms nor the reason(s) why functionally linked to pathways associated with smooth only some people develop HEM are known. Genetic suscepti- muscles, epithelial and endothelial development and bility may play a role in HEM development, but no large-scale, morphogenesis. genome- wide association study (GWAS) for HEM has ever been ► We show genetic correlations of HEM with several other conducted. To evaluate the contribution of genetic variation to diseases that are classified as GI, neuroaffective and the genetic architecture of HEM, we carried out a GWAS meta- cardiovascular disorders. analysis in 218 920 affected individuals and 725 213 population ► We report significance of computed HEM polygenic risk controls of European ancestry. scores, which were validated in independent population- based cohorts. METHODS ► We show significant enrichment of HEM genes in tissue coexpression modules responsible for the development of Detailed methods are provided in the online supplemental mate- musculoskeletal and epidermal systems, and the organisation rial 1 and summarised in the online supplemental figure 3. of the extracellular matrix. ► Based on our data, we outline HEM as a disorder of impaired RESULTS neuromuscular motility, smooth muscle contraction and GWAS meta-analysis and fine-mapping genomic regions http://gut.bmj.com/ extracellular matrix organisation. We conducted a GWAS meta-analysis in 944 133 individuals How might it impact on clinical practice in the foreseeable of European ancestry from five large population- based cohorts 6 7 future? (23andMe, UK Biobank (UKBB), Estonian Genome Centre 8 9 ► The results from this GWAS provide new insights on HEM at the University of Tartu, Michigan Genomics Initiative, and 10 genetic predisposition to smooth muscle, epithelial and Genetic Epidemiology Research on Aging (GERA) ) including connective tissue dysfunction. 218 920 HEM cases and 725 213 controls (online supplemental ► HEM polygenic risk scores identify individuals at risk and table 1). HEM cases had higher body mass index (BMI), were on September 24, 2021 by guest. Protected copyright. correlate with a more severe phenotype. significantly older and more often women compared with non- HEM controls; hence, age, sex, BMI (if available) and top prin- cipal components from principal component analysis (PCA) INTRODUCTION were included as covariates in individual GWAS (see ‘Methods’ Haemorrhoids are normal anal vascular cushions filled with section in online supplemental material 1, hereafter referred to blood at the junction of the rectum and
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