Integrative genomic analyses reveal regional and cellular convergence between uterine fibroids and endometriosis

Abstract Background Uterine fibroids and endometriosis are common oestrogen-responsive gynaecological disorders with partially overlapping inherited susceptibility. The extent to which this overlap is concentrated in specific genomic regions, genes, and reproductive cell types remains incompletely resolved. Methods We integrated publicly available FinnGen Release 9 genome-wide association summary statistics for uterine fibroids (31,661 cases and 179,209 controls) and endometriosis (15,088 cases and 107,564 controls). Genome-wide and local genetic sharing were evaluated using LD Score Regression and LAVA. Gene-level associations were assessed using MAGMA, while published single-cell RNA-sequencing datasets and single-cell-informed stratified LD Score Regression provided cellular context. Selected shared regions were further examined using Bayesian SuSiE fine-mapping. Results The disorders showed a moderate positive genome-wide genetic correlation (rg = 0.511, SE = 0.069, P = 1.37 × 10⁻¹³). Among 92 genomic blocks with valid primary bivariate estimates, 16 remained significant after false-discovery-rate correction, and all had positive local genetic-correlation estimates. MAGMA identified 147 genes associated with uterine fibroids and 38 with endometriosis after Bonferroni correction; ten were significant in both analyses, and seven of these lay within an FDR-significant LAVA region. Single-cell contextualisation and stratified LD Score Regression supported stromal involvement in both disorders, while fine-mapping indicated allelic complexity at selected shared regions. Conclusions Uterine fibroids and endometriosis share a moderate component of common-variant liability, but this overlap is regionally heterogeneous and accompanied by substantial disorder-specific gene-level architecture. Convergence across local genetic correlation, gene-level association and stromal enrichment prioritises reproductive and hormone-responsive regions for independent replication and functional evaluation.