Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
Nat Commun. 2020 Nov 25;11(1):5980. doi: 10.1038/s41467-020-19742-5.
Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.
流产是一种常见且复杂的特征，影响约 15%的临床确诊妊娠。在此，我们呈现了对来自五个不同祖先群体的 69054 例散发性流产、750 例欧洲血统的连续多次（≥3）流产病例和多达 359469 名女性对照的大规模遗传关联分析结果。我们在欧洲血统的荟萃分析中发现了一个与散发性流产具有全基因组显著关联的位点（rs146350366，次要等位基因频率（MAF）为 1.2%，P=3.2×10-8，优势比（OR）=1.4），并在连续多次流产中发现了三个全基因组显著关联的位点（rs7859844，MAF=6.4%，P=1.3×10-8，OR=1.7；rs143445068，MAF=0.8%，P=5.2×10-8，OR=3.4；rs183453668，MAF=0.5%，P=2.8×10-8，OR=3.8）。我们进一步通过基于生物库的孟德尔随机化、遗传度和遗传相关性分析来研究流产的遗传结构。我们的研究结果表明，流产的病因发病机制部分由潜在与胎盘生物学相关的遗传变异驱动，并说明了利用大规模生物库数据来理解这种妊娠并发症的效用。
