Does Depression Increase the Risk of Endometriosis? A Combined Population‑Based and Laboratory Study

Yuru Wang,1,* Zihan Zhu,2,* Xu Jin,3 Zhaoyan Ding,2 Wen Zhong,2 Yueming Zhang,1 Songwei Feng,1,4 Ting Wu1 1Department of Obstetrics and Gynaecology, The Fourth Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China; 2Suzhou Medical College, Soochow University, Suzhou, Jiangsu, People’s Republic of China; 3Department of Pathology, The Fourth Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China; 4Cancer Science Institute of Singapore, National University of Singapore, Singapore*These authors contributed equally to this workCorrespondence: Songwei Feng, Email [email protected] Ting Wu, Email [email protected]: Endometriosis is a chronic, estrogen-dependent inflammatory disorder that causes substantial pain and infertility. Observational studies have reported higher rates of multiple psychiatric disorders among individuals with endometriosis; however, confounding and reverse causation limit causal interpretation.Methods: We performed bidirectional two-sample Mendelian randomization (MR) analyses using genome-wide association study (GWAS) summary statistics from European-ancestry populations to test causal relationships between genetic liability to depression, anxiety, insomnia, bipolar disorder, schizophrenia, and endometriosis. Instrumental variables were selected using genome-wide significance thresholds and linkage disequilibrium clumping, and robustness was evaluated using MR Egger regression, the weighted median method, and mode-based estimators, together with heterogeneity and pleiotropy tests. To assess biological coherence, SH-SY5Y cells were differentiated into sympathetic neuron-like cells, norepinephrine was quantified by enzyme-linked immunosorbent (ELISA) assay, and paracrine effects on 12Z endometriotic epithelial cells were examined using CCK-8 assays. Transcriptomic profiling was followed by Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, and protein–protein interaction (PPI) network analysis.Results: Forward-direction MR supported an association between genetic liability to depression and increased endometriosis risk, whereas anxiety, insomnia, bipolar disorder, and schizophrenia showed no robust causal evidence. Reverse-direction MR did not support endometriosis genetic liability as a causal driver of psychiatric disorders. In vitro, sympathetic neuron-like differentiation increased norepinephrine secretion and enhanced 12Z cell proliferation, with stronger effects under conditioned-medium exposure. Enrichment analyses identified immune-related pathways, with prominent enrichment in Ras signaling, phosphatidylinositol 3 kinase and protein kinase B signaling, mitogen-activated protein kinase signaling, and cyclic adenosine monophosphate signaling.Conclusion: These findings suggest that depression may contribute to endometriosis susceptibility and are supported by complementary in vitro and transcriptomic evidence. This graphical abstract illustrates a potential association between depression and endometriosis identified through Mendelian randomization analysis. ATRA-induced sympathetic-like neurons derived from SH-SY5Y cells show increased norepinephrine production and promote the viability of 12Z endometriotic cells through paracrine signaling. Several signaling pathways may contribute to this process.Infographic: depression-endometriosis link, neuron differentiation, paracrine signaling, MAPK & cAMP key pathways.Keywords: endometriosis, mendelian randomization, RNA-seq, depression, GWAS