Abstract
We conducted a multi-ancestry genome-wide association study of endometriosis and adenomyosis in almost 1.4 million women, including 105,869 cases, aiming to expand endometriosis loci discovery across ancestries, dissect symptom-specific effects, and integrate multi-omic data. We identified 80 genome-wide significant associations, 37 of which are novel, including five loci that are the first ever variants reported for adenomyosis. Fine-mapping and colocalization analyses uncovered causal loci for over 50 endometriosis-related associations. Multi-omics integration revealed that genetic variation influences endometriosis risk through transcriptomic, epigenetic, and proteomic regulation across multiple tissues, converging on pathways involved in immune regulation, tissue remodeling, and cell differentiation. Drug-repurposing analyses highlighted potential therapeutic interventions currently used for breast cancer and preterm birth prevention. Endometriosis polygenic risk interacted with abdominal pain, anxiety, migraine, and nausea. This study advances the understanding of genetic risk factors for endometriosis and provides molecular support for several hypotheses on the disease pathogenesis.