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

Hemorrhoidal disease (HEM) affects a large fraction of the population but its etiology including suspected genetic predisposition is poorly understood. We conducted a GWAS meta-analysis of 218,920 HEM patients and 725,213 controls of European ancestry, demonstrating modest heritability and genetic correlation with several other diseases from the gastrointestinal, neuroaffective and cardiovascular domains. HEM polygenic risk scores 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 harboring genes whose expression is enriched in blood vessels and gastrointestinal tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses of affected tissue from HEM patients highlighted HEM gene co-expression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organization of the extracellular matrix. We conclude HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This project was funded by Andre Franke's and Clemens Schafmayer's DFG grant "Discovery of risk factors for hemorrhoids" (ID: FR 2821/19-1). The study received infrastructure support from the DFG Cluster of Excellence 2167 "Precision Medicine in Chronic Inflammation (PMI)" (DFG Grant: EXC2167). The project was supported by grants from the Swedish Research Council to MD (VR 2017-02403), the Novo Nordisk Foundation (grants NNF17OC0027594 and NNF14CC0001) and BigTempHealth (grant 5153-00002B). The work on cross-trait analysis for diverticular disease presented in this manuscript was supported by the German Research Council (DFG, ID: Ha3091/9-1) and the Austrian Science Fund (FWF, ID: I1542-B13). EGCUT work has also been supported by the European Regional Development Fund and grants SP1GI18045T, No. 2014-2020.4.01.15-0012 GENTRANSMED and 2014-2020.4.01.16-0125. This study was also funded by EU H2020 grant 692145 and Estonian Research Council Grant PUT1660. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The enrolment of study participants was approved by the ethics committees or institutional review boards of all individual participating centers or countries. Written informed consent was obtained from all study participants. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data supporting the findings described in this study are available from the corresponding author upon request.