ObjectiveEndometriosis 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).DesignA two‐sample MR study.SettingSummary statistics from published GWASs on European ancestry populations for endometriosis and gestational duration.Population or SampleInstrumental variables for endometriosis were derived from a meta‐analysis comprising 60 674 endometriosis cases and 701 926 controls.MethodsGenetic 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 MeasuresPrimary outcomes were gestational duration and preterm birth, sourced from the latest GWAS data.ResultsLD 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.ConclusionsContrary 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.

中文翻译：

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子宫内膜异位症相关遗传因素及其在早产中的作用：一项双样本孟德尔随机化研究


目的子宫内膜异位症影响全球 10% 的女性，并与不良妊娠结局有关，包括早产。最近的流行病学和遗传学研究表明，子宫内膜异位症可能会影响孕期和早产的可能性。本研究旨在利用来自最近全基因组关联研究 （GWAS） 的遗传数据，使用孟德尔随机化 （MR） 分析估计子宫内膜异位症对孕期和早产的直接遗传因果影响。设计一项双样本 MR 研究。设置已发表的 GWAS 关于子宫内膜异位症和孕期欧洲血统人群的摘要统计数据。子宫内膜异位症的人群或样本工具变量来自一项荟萃分析，包括 60 674 例子宫内膜异位症病例和 701 926 例对照。方法使用连锁不平衡评分回归计算遗传相关性和遗传力估计值。具有乘法随机效应逆方差加权的双样本 MR 评估了主要目标，并辅以敏感性分析以验证 MR 假设。主要结局指标主要结局是胎龄和早产，来源于最新的 GWAS 数据。结果LD 评分回归显示子宫内膜异位症与胎期或早产之间无遗传相关性。MR 分析显示子宫内膜异位症与母体对后代胎期 （β = 0.40,95% CI： -0.39 至 1.19，p = 0.32） 或早产 （OR = 0.94,95% CI： 0.82–1.06，p = 0.36） 的影响之间没有因果关系。敏感性分析表明多效性，但没有违反 MR 假设。 在孕期和子宫内膜异位症 GWAS 之间重叠的四个基因座中，使用 MR-Presso 将三个 （EBF1、WNT4 和 GDAP1） 确定为异常值。结论与观察性研究相反，MR 分析发现子宫内膜异位症与胎期或早产之间没有直接的因果关系。基因组区域的重叠表明这种关系可能是通过不同的生物途径介导的。