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

Feng S, Wang Y, Liu S, Zhang Y, He L
2025 · W7018077575
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This large-scale genetic-driven observational study used Mendelian randomization with 191 resting-state fMRI phenotypes and endometriosis genetic datasets, applying forward and reverse MR plus sensitivity analyses to test robustness. Forward MR found three brain networks (Pheno20, Pheno38, Pheno44) associated with endometriosis risk, with Pheno38 inversely linked to fallopian tube endometriosis and Pheno20/Pheno44 positively linked to adenomyosis. Reverse MR reported that ovarian endometriosis was inversely associated with functional connectivity in Pheno932, a network related to cognitive and attention processes, with sensitivity analyses supporting the reliability of these findings. This paper is centrally about endometriosis — it uses Mendelian randomization to identify causal links between brain functional networks and endometriosis (including subtype-specific effects) and reports positive links to adenomyosis.

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Abstract

Songwei Feng,1,* Yuru Wang,1,* Sicong Liu,2,* Yueming Zhang,1 Leilei He1 1Department of Obstetrics and Gynaecology, The Fourth Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of Obstetrics and Gynaecology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Leilei He, Email [email protected]: 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.Keywords: endometriosis, brain functional networks, resting-state fMRI, Mendelian randomization
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International Journal of Women's Health (Feb 2025) Causal Links Between Brain Functional Networks and Endometriosis: A Large-Scale Genetic-Driven Observational Study Abstract Songwei Feng,1,* Yuru Wang,1,* Sicong Liu,2,* Yueming Zhang,1 Leilei He1 1Department of Obstetrics and Gynaecology, The Fourth Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of Obstetrics and Gynaecology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Leilei He, Email [email protected]: 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.Keywords: endometriosis, brain functional networks, resting-state fMRI, Mendelian randomization

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