Endometriosis is one of the most common underrepresented medical issues facing one in seven Australian women. The disease has profound impacts on women’s health, employment and reproductive outcomes costing the Australian economy $9.7 billion/year. There are limited effective diagnostic and treatment options and slow progress towards improving patient outcomes. The disease exhibits significant heterogeneity, with poor relationships between symptoms, disease severity and clinical presentation. Symptoms can span multiple body systems including urogenital, gastrointestinal and neurological and often overlap with other conditions making diagnosis challenging. This heterogeneity contributes to diagnostic delays, unnecessary surgeries, misdiagnosis and variable treatment response. To better understand factors contributing disease risk and variability we aimed to identify and characterise endometriosis comorbidities.

Using medical records and genetic data from 5,432 endometriosis cases and 92,344 controls from the UK Biobank we identified a significant association between an endometriosis diagnosis and 292 other diagnostic codes, spanning gynaecological, immune, pain, psychiatric, gastrointestinal and urinary systems. Similarly, we found a relationship between a genetic liability of endometriosis and a subset of these conditions, with the importance of female-specific pathways underscored by the absence of replication in males carrying endometriosis risk variants. Most comorbidities could be attributed to shared genetics, with one novel causal effect of testosterone levels discovered. We observed a striking increase in the number of comorbidities reported for individuals with endometriosis compared to those without highlighting a heightened disease burden in these individuals that likely contributes to the variability in symptoms and treatment outcomes.

Endometriosis is comorbid, and shares a genetic architecture, with conditions across diverse biological systems. Despite limited evidence of individual traits causing endometriosis, there are overlapping biological pathways and the cumulative burden of conditions influence endometriosis risk. These findings offer valuable insights into endometriosis aetiology and hold clinical implications for endometriosis diagnosis and management decisions.