Pathogenesis of Endometriosis: Genetics

Endometriosis is a complex condition that is caused by both multiple genetic and environmental factors. The heritable component for endometriosis is estimated at ~50%. Here we provide a summary of genome-wide associations studies (GWAS) performed to date to identify common genetic variants for endometriosis. Largest GWAS meta-analysis conducted by the International Endogene Genomics Consortium (IEGC) included a total of 58, 115 endometriosis cases and 733, 480 controls and has identified 27 loci genome-wide significantly associated with endometriosis. Positionally, the lead SNPs for the identified genetic loci reside near genes that are involved in sex-steroid hormone, WNT signaling, cell adhesion/migration, cell growth/carcinogenesis, and inflammation-related pathways. Furthermore, genetic variants associated with subtypes of endometriosis are described. In particular, eight genome-wide significant signals were associated with stage III/IV disease and 21 of 27 loci had larger effect sizes in stage III/IV disease compared to stage I/II disease suggesting that particular variants may confer risk for different subtypes of endometriosis through different pathways. Together, the 27 loci explained 2.15% of variance for overall endometriosis and 3.83% for stage III/IV disease which highlight that there remain many more genetic loci to be revealed for endometriosis in larger, deeply phenotyped datasets. Furthermore, future research needs to focus on fine-mapping of the identified loci to reveal the causal variants for each of the 27 loci and functional follow-up examining their effects on multiomics data in tissues and cells relevant to endometriosis, i.e., endometrium and its cellular components.