Comorbidity of endometriosis and uterine fibroid: genetic insights from cohort analysis

Objective: Endometriosis (EM) and uterine leiomyoma (UL) are common gynecological disorders with substantial clinical overlap; however, their shared epidemiological and genetic underpinnings remain poorly understood. This study investigated comorbidity between EM and UL using epidemiological, genetic, and molecular analyses. Methods: We performed cross-sectional analyses using National Health and Nutrition Examination Survey (NHANES) data ( n = 1,466) to assess comorbidity risk. Shared genetic loci were identified through colocalization analysis of genome-wide association study summary statistics. Differential expression analysis and gene set enrichment analysis (GSEA) were conducted using Gene Expression Omnibus (GEO) datasets to explore underlying molecular mechanisms. Results: In the NHANES cohort, 2.7% of participants had both EM and UL conditions. Strong comorbidity was observed (weighted odds ratio = 4.14, 95% confidence interval: 2.41–7.11, P = 2.62×10⁻ 7 ). Colocalization analysis identified two shared loci, wingless-type MMTV integration site family member 4 (WNT4; rs2235529) and spectrin repeat containing nuclear envelope protein 1 (SYNE1; rs58415480), with a high probability of colocalization (PPH 4 > 0.80). WNT4 was significantly upregulated in both EM and UL lesions at the transcriptomic level, which was enriched in pathways, including cell junction assembly and collagen metabolism, in both diseases. Conclusions: EM and UL exhibit pronounced epidemiological comorbidity and shared genetic susceptibility; WNT4 and SYNE1 were identified as strong candidate genes. Dysregulation of WNT4 -mediated pathways may contribute to disease co-occurrence. These findings suggest promising directions for future research into common pathogenic mechanisms and highlight the potential of WNT4 as a candidate target for further investigation.