Causal Relationship Between Socioeconomic Inequality and Hormone-Related Gynecologic Diseases: A Two-Sample, Two-Step Mendelian Randomization Study

Yi Yu,* Zhonghao Mao,* Lianlian Feng, Nannan Li, Xinlin Jiao, Teng Zhang, Baoxia Cui Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Baoxia Cui, Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, No. 107 Wenhua West Road, Jinan, Shandong, 250012, People’s Republic of China, Tel +86 185 6008 1862, Email [email protected]: Although observational studies suggest a link between socioeconomic status (SES) and hormone-related gynecologic diseases, the causal direction and mediating mechanisms remain unclear. This study aims to explore the causal relationships and potential mediators using genetic data.Patients and Methods: We conducted univariable and multivariable Mendelian randomization (UVMR and MVMR) analyses using genome-wide association study (GWAS) summary statistics from European populations to assess the causal effects of education, income, and occupation on five hormone-related gynecologic diseases. A two-step MR was applied to explore potential mediators.Results: Genetically predicted higher educational attainment, but not income or occupation, showed the protective causal effect on the risk of endometriosis. In UVMR and MVMR analyses, a genetic predisposition for higher education was found to be causally associated with reduced rates of endometriosis (UVMR: OR = 0.94, 95% CI: 0.91– 0.98, P = 0.001; MVMR: OR = 0.92, 95% CI: 0.87– 0.98, P = 0.018) and uterine endometriosis (UVMR: OR = 0.91, 95% CI: 0.86– 0.98, P = 0.007; MVMR: OR = 0.88, 95% CI: 0.80– 0.96, P = 0.006). Mediation analysis indicated that major depression (MDD) might play a potential, causal mediating role between education and uterine endometriosis, with a mediation proportion of 12.22%.Conclusion: These findings provide genetic evidence that educational attainment reduces the risk of uterine endometriosis, partly through MDD. Targeted public health strategies addressing education and mental health may help reduce disease burden.Keywords: socioeconomic status, educational attainment, endometriosis, Mendelian randomization, major depression, female reproductive health