Evidence of shared genetic factors in the aetiology of gastrointestinal disorders and endometriosis and clinical implications for disease management

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. WHAT IS ALREADY KNOWN ON THIS TOPIC?O_LIBoth endometriosis and gastrointestinal disorders affect a large proportion of people worldwide and the co-existence of endometriosis and gastrointestinal symptoms (eg, abnormal pain, bloating, constipation) is often observed in clinical practice. C_LIO_LIThe association of these two diseases was supported but also limited to previous observational evidence which highlights a three-fold increase in the prevalence of irritable bowel syndrome (IBS) in women with endometriosis. C_LIO_LIObservational study is easily subject to measurement error, confounding and reverse causation. Therefore, it is important to assess the association using multidimensional datasets and more accurate approaches, such as the use of genetic data in a mendelian randomisation framework as well as the analysis from a perspective of medication usage. C_LI WHAT THIS STUDY ADDSO_LIGenetic risk factors for endometriosis and gastrointestinal disorders, two leading causes of discomfort and chronic pelvic pain, are correlated. C_LIO_LIMendelian randomisation analyses supported a causal relationship between genetic predisposition to gastrointestinal disorders (gastro-oesophageal reflux disease (GORD) and peptic ulcer diseases (PUD)) and endometriosis risk, and evidence for a bidirectional causal relationship between endometriosis and IBS, which might explain in part the co-occurrence of these diseases. C_LIO_LIThe identification of shared risk loci highlighted biological pathways that may contribute to the pathogenesis of both diseases, including estrogen regulation and inflammation, as well as potential therapeutic drug targets such as CCKBR and PDE4B. C_LIO_LIThe higher use of drugs for IBS, GORD and PUD in women diagnosed with endometriosis as well as the higher use of hormone therapies in women diagnosed with IBS, GORD and PUD, support the co-occurrence of these conditions and shared disease aetiology but also highlights the potential for drug repositioning and caution around drug contraindications. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/22281201v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1a85d4forg.highwire.dtl.DTLVardef@8623baorg.highwire.dtl.DTLVardef@939f2corg.highwire.dtl.DTLVardef@1b70f55_HPS_FORMAT_FIGEXP M_FIG C_FIG