Expanding the genetic landscape of endometriosis: Integrative -omics analyses specify key pathways from a multi-ancestry study of over 900,000 women

We report the findings of a genome-wide association study (GWAS) meta-analysis of endometriosis across 14 biobanks worldwide, including 32% non-European patient participants, as part of the Global Biobank Meta-Analysis Initiative (GBMI). Out of 58 total loci (29 previously unreported), the largest meta-analysis accounted for 46 (20 previously unreported). We detected the first genome-wide significant loci (2p13.3 and 20q13.2) uniquely driven by the African-ancestry meta-analysis. Our imaging- and surgery-confirmed phenotypes yielded six additional previously unreported loci. Leveraging our large and diverse study population, we observed SNP heritability estimates of 9-13% for all ancestry groups, and 13 loci had at least one variant in the credible set after fine-mapping. Investigating the complex array of endometriosis comorbidities and risk factors revealed 135 genetically correlated phenotypes and 95 with evidence of vertical pleiotropy, including triglycerides and anxiety disorders. We prioritized 35 disease-relevant cellular contexts from the endometrial cell atlas and found 322 examples of differentially expressed genes in cells from donors with endometriosis. Further high-throughput multi-omic analyses implicated a total of 282 genes in endometriosis pathogenesis. Our diverse, comprehensive GWASs, with downstream analyses spanning molecular to phenotypic scales, provide detailed evidence for aspects of endometriosis including the role of immune cell types, Wnt signaling, and cellular proliferation. These interconnected pathways and risk factors underscore the complex, multi-faceted etiology of endometriosis, suggesting multiple targets for precise and effective therapeutic interventions.