Causal Links Between Brain Functional Networks and Endometriosis: A Large-Scale Genetic-Driven Observational Study

Introduction: Endometriosis is a chronic gynecological disorder that significantly impacts women of reproductive age. Recent evidence suggests a bidirectional link between endometriosis and brain functional networks, though the causal mechanisms remain unclear. This study aims to explore these relationships using Mendelian Randomization (MR) analysis. Methods: Data from 191 resting-state functional MRI (rsfMRI) phenotypes and endometriosis genetic datasets were analyzed using both forward and reverse MR approaches. Genetic Instrument Selection was performed to identify valid instrumental variables, ensuring their independence from confounders and strong association with the exposure. Sensitivity analyses were conducted to ensure the robustness of the findings. Results: Forward MR analysis identified three brain networks (Pheno20, Pheno38, Pheno44) significantly associated with endometriosis risk (P FDR < 0.05). Notably, Pheno38 activity was inversely associated with fallopian tube endometriosis, whereas Pheno20 and Pheno44 were positively linked to adenomyosis. Reverse MR analysis revealed that endometriosis of the ovary was inversely associated with functional connectivity in Pheno932, a network involved in cognitive and attention processes. Sensitivity analyses confirmed the reliability of these results. Discussion: This study highlights a complex bidirectional relationship between brain functional networks and endometriosis. Increased activity in specific networks may protect against or predispose individuals to certain subtypes of endometriosis. Conversely, endometriosis also can influence brain connectivity, potentially contributing to cognitive and emotional symptoms.