Expanding the genetic landscape of endometriosis: Integrative -omics analyses uncover key pathways from a multi-ancestry study of over 900,000 women
Guare LA,
Lindsay Guare,
Jagyashila Das,
Das J,
Lannawill Caruth,
Caruth L,
Ananya Rajagopalan,
Rajagopalan A,
Akerele AT,
Alexis T Akerele,
Brumpton BM,
Ben M Brumpton,
Chen T,
Tzu-Ting Chen,
Leah Kottyan,
Kottyan L,
Kuang Lin,
Lin Y,
Elisa Moreno,
Moreno E,
Mulford AJ,
Ashley J Mulford,
Vita Rovite,
Dombrovska MS,
Luo Y,
Alan R Sanders,
Rovite V,
Marija Simona Dombrovska,
Sanders AR,
Noemie Elhadad,
Andrew Hill,
Teerlink C,
Gail Jarvik,
Candelieri D,
Elhadad N,
James Jaworski,
Yuan Luo,
Hill A,
Shinichi Namba,
Jarvik GP,
Yukinori Okada,
Jaworski J,
Lynch J,
Yue Shi,
Namba S,
Yuya Shirai,
Jonathan Shortt,
Okada Y,
Wei-Qi Wei,
Shi Y,
Shirai Y,
Chunhua Weng,
Shortt J,
Yuji Yamamoto,
Wei W,
Sinead Chapman,
Wei Zhou,
Weng C,
Yamamoto Y,
Digna R. Velez Edwards,
Shefali S. Verma,
Chapman S,
Zhou W,
Chang K,
Edwards T,
Senapati S,
Velez Edwards DR,
Setia-Verma S
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This multi-ancestry genome-wide association study meta-analysis identified 45 significant endometriosis loci, including seven novel ones, and integrated -omics data to reveal roles for immunopathogenesis and Wnt signaling.
Abstract
We report the findings of a genome-wide association study (GWAS) meta-analysis of endometriosis consisting of a large portion (31%) of non-European samples across 14 biobanks worldwide as part of the Global Biobank Meta-Analysis Initiative (GBMI). We identified 45 significant loci using a wide phenotype definition, seven of which are previously unreported and detected first genome-wide significant locus ( POLR2M ) among only African-ancestry. Our narrow phenotypes and surgically confirmed case definitions for endometriosis analyses replicated the known loci near CDC42 , SKAP1 , and GREB1 . Through this large ancestry stratified analyses, we document heritability estimates in range of 10-12% for all ancestral groups. Thirty-eight loci had at least one variant in the credible set after fine-mapping. An imputed transcriptome-wide association study (TWAS) identified 11 associated genes (two previously unreported), while the proteome-wide association study (PWAS) suggests significant association of R-spondin 3 (RSPO3) with wide endometriosis, which plays a crucial role in modulating the Wnt signaling pathway. Our diverse, comprehensive GWAS, coupled with integrative -omics analysis, identifies critical roles of immunopathogenesis, Wnt signaling, and balance between proliferation, differentiation, and migration of endometrial cells as hallmarks for endometriosis. These interconnected pathways and risk factors underscore a complex, multi-faceted etiology of endometriosis, suggesting multiple targets for precise and effective therapeutic interventions.
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- last seen: 2026-10-27T06:35:58.866613+00:00
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