Multi-ancestry genome-wide association and integrated multi-omics analyses of endometriosisand its clinical manifestations<br />

Abstract

Endometriosis is a chronic systemic disease affecting ~10%women, yet its geneticbasis and molecular mechanisms remain poorlyunderstood. Hence, we conducted a genome-wide association study of endometriosis and adenomyosis in ~1.4 million women, including 105,869cases, aiming to expand locidiscovery across ancestries, dissect symptom-specific effects and integratemulti-omic data. We identified 80 genomic regions associated with endometriosis risk,including 37 new loci, and 5 of which are alsoassociated with adenomyosis. We identified putativecausal variants underlying over 50 of these associations. Transcriptomic, epigenetic and proteomic analyses across tissueslinked endometriosis risk to pathways involved in cell differentiation, immune and hormonalregulation, tissue remodeling and inflammation. Drug-repurposing analyses highlighted potential treatments currently used for breastcancer, contraception and preterm birthprevention. Endometriosis polygenic risk interacted with abdominal pain, anxiety, migraineand nausea. This study advances understanding of genetic risk factors for endometriosis and provides molecular support for several hypotheses on its pathogenesis.