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. 2025 May;132(6):762-769.
doi: 10.1111/1471-0528.18039. Epub 2024 Dec 5.

Endometriosis-Related Genetic Factors and Their Role in Preterm Birth: A Two-Sample Mendelian Randomisation Study

Christopher Flatley  1 , Dana Kristjansson  2   3 , Karin Ytterberg  4 , Julius Juodakis  4 , Pol Sole-Navais  4 , Bo Jacobsson  4   5   6
Affiliations

Endometriosis-Related Genetic Factors and Their Role in Preterm Birth: A Two-Sample Mendelian Randomisation Study

Christopher Flatley et al. BJOG. 2025 May.

Abstract

Objective: Endometriosis affects 10% of women worldwide and is linked to adverse pregnancy outcomes, including preterm birth. Recent epidemiological and genetic studies indicate that endometriosis may influence gestational duration and the likelihood of preterm birth. This study aimed to estimate the direct genetic causal effects of endometriosis on gestational duration and preterm birth using Mendelian randomisation (MR) analysis, leveraging genetic data from recent genome-wide association studies (GWASs).

Design: A two-sample MR study.

Setting: Summary statistics from published GWASs on European ancestry populations for endometriosis and gestational duration.

Population or sample: Instrumental variables for endometriosis were derived from a meta-analysis comprising 60 674 endometriosis cases and 701 926 controls.

Methods: Genetic correlations and heritability estimates were calculated using linkage disequilibrium score regression. Two-sample MR with multiplicative random-effects inverse variance weighting assessed the primary objectives, supplemented by sensitivity analyses to validate MR assumptions.

Main outcome measures: Primary outcomes were gestational duration and preterm birth, sourced from the latest GWAS data.

Results: LD score regression revealed no genetic correlation between endometriosis and either gestational duration or preterm birth. MR analysis showed no causal association between endometriosis and maternal effects on offspring gestational duration (β = 0.40, 95% CI: -0.39 to 1.19, p = 0.32) or preterm birth (OR = 0.94, 95% CI: 0.82-1.06, p = 0.36). Sensitivity analyses indicated pleiotropy but no violations of MR assumptions. Of the four loci overlapping between the gestational duration and endometriosis GWASs, three (EBF1, WNT4, and GDAP1) were identified as outliers using MR-Presso.

Conclusions: Contrary to observational studies, MR analyses found no direct causal link between endometriosis and gestational duration or preterm birth. Overlaps in genomic regions suggest that the relationship may be mediated through different biological pathways.

Keywords: endometriosis; genetic correlation; genetics; genomics; gestational age; gynaecology; mendelian randomisation; obstetrics; preterm birth.

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