Genomic characterisation of the overlap of endometriosis with 76 comorbidities identifies pleiotropic and causal mechanisms underlying disease risk

Abstract

Comorbid conditions can be driven by underlying pleiotropic and causal mechanisms that can provide insights into shared molecular and biological processes contributing to disease risk. Endometriosis is a chronic condition affecting one in nine women of reproductive age and poses many challenges including lengthy diagnostic delays and limited treatment efficacy owing to poor understanding of disease aetiology. To shed light on the underlying biological mechanisms and to identify potential risk factors, we examine the epidemiological and genomic relationship between endometriosis and its comorbidities. In the UK Biobank 292 ICD10 codes were epidemiologically correlated with endometriosis diagnosis, including gynaecological, immune, infection, pain, psychiatric, cancer, gastrointestinal, urinary, bone and cardiovascular traits. A subset of the identified comorbidities (n = 76) underwent follow-up genetic analysis. Whilst Mendelian randomisation suggested causality was not responsible for most comorbid relationships, 22 traits were genetically correlated with endometriosis, including pain, gynaecological and gastrointestinal traits, suggestive of a shared genetic background. Pleiotropic genetic variants and genes were identified using gene-based and colocalisation analysis. Shared genetic risk factors and potential target genes suggest a diverse collection of biological systems are involved in these comorbid relationships including coagulation factors, development of the female reproductive tract and cell proliferation. These findings highlight the diversity of traits with epidemiological and genomic overlap with endometriosis and implicate a key role for pleiotropy in the comorbid relationships.

Polygenic risk score phenome-wide association study reveals an association between endometriosis and testosterone

“…Given these individuals did not have a history of endometriosis, the association of abdominal pain with the endometriosis PRS must be explained by factors beyond presence of the lesion. A shared genetic background has previously been identified between endometriosis and multiple pain traits [ 3 , 5 ]. Multiple other traits previously identified to have a shared genetic background with endometriosis were significant in the female analysis but not the male analysis.…”

Effects of the gut microbiota and its metabolite short-chain fatty acids on endometriosis

“…Currently, EMS is mainly confirmed through invasive procedures such as laparoscopy and histopathology EMS ( Agarwal et al., 2019 ). Because EMS is often associated with gynecological, pain, and gastrointestinal disorders, its non-specific manifestations and highly limited diagnostic methods lead to delayed diagnosis and treatment of EMS ( Arruda et al., 2003 ; McGrath et al., 2023 ). Conventional treatment with EMS (such as surgery and hormone therapy) can relieve associated symptoms ( Bedaiwy et al., 2017 ).…”