Expanding the genetic landscape of endometriosis: Integrative -omics analyses implicate key genes and pathways in a multi-ancestry study of over one million women

This is the authors' abstract. We don't add key points for this paper.

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). Eleven meta-analyses detected 58 total associated regions (27 previously unreported), including six yielded by imaging- and surgery-confirmed phenotypes. We detected the first genome-wide significant loci uniquely driven by the African-ancestry (1q42. 13, 2p13 . 3 , and 20q13 . 2 ) and Admixed-American-ancestry ( 21q22 . 13 ) meta-analyses. Leveraging our large and diverse study population, we observed SNP heritability estimates of 9-13% for all ancestry groups, and 14 regions 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. Including further high-throughput multi-omic analyses, we have implicated a total of 314 genes in endometriosis pathogenesis. This 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 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.