Abstract Background Population studies elucidating the genetic architecture of endometriosis have predominantly focused on individuals of European ancestry, thereby leaving a gap in understanding the genetic influences within non-European populations. This present study aims to identify potential genetic variants associated with endometriosis in Iranian women. Research design and methods We conducted a genome-wide association study on endometriosis involving a discovery group of 1978 women, comprising 305 women with endometriosis and 1673 unaffected individuals. An independent confirmation cohort comprising 829 women (101 cases and 728 controls) was selected from the TCGS cohort. Over 9 million genetic variants were analyzed using the Genome-wide Complex Trait Analysis framework, followed by integrative bioinformatics and functional annotation analyses. Results In the discovery phase, we identified rs12886544 at the GNPNAT1 locus as genome-wide significant for endometriosis susceptibility (OR = 1.66, p -value = 5.89 × 10⁻⁸). In the confirmation cohort, the direction of effect was consistent with the discovery phase, although the association did not remain statistically significant after correction for multiple testing (OR = 1.4, 95% CI 0.89–2.11, p = 0.14). A pooled analysis of the discovery and confirmation cohorts demonstrated a statistically significant association between rs12886544 and endometriosis risk (combined p -value = 0.001, OR = 1.59, 95% CI 1.19–1.89). Epigenomics results suggest that rs12886544 may affect a regulatory motif associated with the Bobby Sox homolog (BBX) transcription factor in women, implicating a potential role in modulating gene expression. Conclusions Our findings provide supportive evidence that rs12886544 at the GNPNAT1 locus is associated with endometriosis susceptibility in Iranian women. The association was supported by a consistent direction of effect in an independent cohort and a significant pooled analysis, although further validation in larger independent populations is required. Additionally, observed differences in allele frequencies between Iranian and European populations highlight the importance of trans-ethnic studies for understanding population-specific genetic architecture in endometriosis. Graphical abstract
Najd-Hassan-Bonab et al. (Wed,) studied this question.