Shared Genetic Architecture Between Endometriosis and Psychiatric Conditions May Explain Comorbidity

Endometriosis is a common chronic gynecological disorder with complex and poorly understood etiology and no definitive cure. Beyond pain and infertility, affected individuals frequently experience psychiatric comorbidities, often attributed to the burden of chronic symptoms. Emerging evidence suggests this explanation is incomplete, and shared biological mechanisms may also contribute. Here, we integrate large-scale genomic data to characterize the genetic overlap between endometriosis and a broad spectrum of psychiatric conditions. We found no evidence that genetic liability to endometriosis increases the risk of psychiatric conditions. In contrast, genetic liability to psychiatric conditions, particularly major depressive disorder and related traits, was associated with increasing the risk of endometriosis. Polygenic analyses revealed extensive shared genetic architecture, with nearly all variants influencing endometriosis also implicated in depression. Leveraging this overlap in a multivariate GWAS, we identify 606 independent genome-wide significant variants contributing to shared liability and implicate convergent biological pathways - particularly brain-related mechanisms - providing a foundation for mechanistic studies and potential strategies to mitigate psychiatric comorbidity in endometriosis.