Miscarriage is a common adverse pregnancy outcome, impacting approximately 15% of pregnancies. Herein, we present results of the largest trans-ancestral genome wide association study for miscarriage to date, based on 334,593 cases of sporadic, and 52,087 cases of recurrent miscarriage in the 23andMe, Inc. Research Cohort. We identified 10 novel genome-wide significant associations for sporadic miscarriage, and one for recurrent miscarriage. These loci mapped to genes with roles in neural development and telomere length, and to developmental disorders including autism spectrum disorder. Three variants, with similar directionality and magnitude of effect, replicated in a previously published GWAS. Using Mendelian randomization and triangulation, robust evidence was found for smoking causally increasing the risk of sporadic (genetic liability to ever vs never smoking: OR 1.13; 95%CI: 1.11-1.15; P=2.61e-42) and recurrent (OR 1.25; 95%CI: 1.21-1.30; P=5.47e-34) miscarriage, with moderate, yet triangulating, evidence identified for a potential etiological role of caffeine consumption.

中文翻译：

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偶发性和复发性流产的跨祖先基因组广泛关联研究

流产是一种常见的不良妊娠结局，影响约 15% 的妊娠。在此，我们展示了迄今为止最大的流产跨祖先基因组广泛关联研究的结果，该研究基于 23andMe, Inc. 研究队列中的 334,593 例散发性流产病例和 52,087 例复发性流产病例。我们发现了 10 种新的全基因组范围内与偶发性流产的显着关联，以及一种与复发性流产的显着关联。这些基因座映射到在神经发育和端粒长度中发挥作用的基因，以及包括自闭症谱系障碍在内的发育障碍。具有相似方向性和影响程度的三种变体在之前发布的 GWAS 中得到了复制。使用孟德尔随机化和三角测量，发现吸烟会增加散发性（曾经吸烟与从不吸烟的遗传倾向：OR 1.13；95%CI：1.11-1.15；P=2.61e-42）和复发性（OR 1.25）的风险。 ; 95%CI: 1.21-1.30; P=5.47e-34) 流产，有中度但三角测量的证据表明咖啡因摄入的潜在病因作用。