In clinical practice, the co-existence of endometriosis and gastrointestinal symptoms is often observed; however, the factors driving this link remain largely unknown. Here, using large-scale multifaceted data including observational, genetic, and pharmaceutical datasets, we report a positive phenotypic and genetic association of endometriosis with peptic ulcer disease (PUD), gastro-oesophageal reflux disease (GORD), a combined GORD/PUD Medicated (GPM) phenotype and irritable bowel syndrome (IBS), but not with inflammatory bowel disease (IBD). Mendelian randomization analysis identified a causal effect of the GPM phenotype on endometriosis and a bidirectional causal association between endometriosis and IBS. Cross-trait meta-analysis and colocalization along with comprehensive functional annotation confirmed two shared genetic loci (FN1, TACSTD2) for endometriosis with IBS and twelve loci (ETAA1, HOXC4, RERG, SEMA3F, SPAG16, HIST1H2BC, RAB5B, CCKBR and PDE4B) with GORD and PUD. Shared genetic loci may contribute to risk of both endometriosis and digestive disorders through the involvement of DNA damage, estrogen regulated cell-proliferation and inflammation, and barrier dysfunction. Analyses of medication usage identified a higher use of drugs for IBS, GORD and PUD in women diagnosed with endometriosis as well as a higher use of hormone therapies in women diagnosed with IBS, GORD and PUD but not for IBD, which strongly supports the co-occurrence of these conditions and highlights the potential for drug repositioning and caution around drug contraindications in clinical practice. Taken together, the combined evidence robustly suggests a shared disease aetiology and provides important clinical implications for diagnostic and treatment decisions for endometriosis and digestive disorders.

The authors have declared no competing interest.

This work was supported by the National Health and Medical Research Council of Australia [Project Grants GNT1147846, GNT1105321 and GNT1049472, Investigator Grant 1177194 to G.W.M and Medical Research Future Fund Research Grant MRF1199785 to G.D.M and S.M]. For funding details of the endometriosis meta-analysis please see Sapkota et al., (2017).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

UK Biobank had obtained ethics approval from the North West Multi-centre Research Ethics Committee which covers the UK (approval number: 11/NW/0382) and had obtained informed consent from all participants. The UK Biobank approved an application for use of the data (ID 12505 and 54861) and ethics approval for the analyses was obtained from the Human and Research Ethics Committees (HREC) of the University of Queensland (2020/HE002852). ALSWH was originally approved by the Human and Research Ethics Committees (HREC) of the University of the Newcastle (UoN) in 1995 (Clearance number: H 076 0795) and by The University of Queensland (UQ) in 2004 (reference number: 2004 000 224). The most recent amendment for ALSWH Survey 8 of the 1973-78 cohort was approved by UoN HREC on 8 November 2017 and ratified by UQ HREC on 9 November 2017. Ethical approval for data linkage was obtained from the UoN HREC on 31 January 2012 (Clearance Number: H-2011-0371) and from the UQ HREC on 9 February 2012 (Number: 2012000132).

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