BACKGROUND Preterm birth (<37 weeks of gestation) is a major cause of neonatal death and morbidity. Up to 40% of the variation in timing of birth results from genetic factors, mostly due to the maternal genome. METHODS We conducted a genome-wide meta-analysis of gestational duration and spontaneous preterm birth in 68,732 and 98,370 European mothers, respectively. RESULTS The meta-analysis detected 15 loci associated with gestational duration, and four loci associated with preterm birth. Seven of the associated loci were novel. The loci mapped to several biologically plausible genes, for example HAND2 whose expression was previously shown to decrease during gestation, associated with gestational duration, and GC (Vitamin D-binding protein), associated with preterm birth. Downstream in silico-analysis suggested regulatory roles as underlying mechanisms for the associated loci. LD score regression found birth weight measures as the most strongly correlated traits, highlighting the unique nature of spontaneous preterm birth phenotype. Tissue expression and colocalization analysis revealed reproductive tissues and immune cell types as the most relevant sites of action. CONCLUSION We report novel genetic risk loci that associate with preterm birth or gestational duration, and reproduce findings from previous genome-wide association studies. Altogether, our findings provide new insight into the genetic background of preterm birth. Better characterization of the causal genetic mechanisms will be important to public health as it could suggest new strategies to treat and prevent preterm birth.

中文翻译：

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对妊娠持续时间和自发性早产的全基因组关联研究的荟萃分析确定了新的孕产妇风险位点。

背景技术早产（妊娠<37周）是新生儿死亡和发病的主要原因。高达 40% 的出生时间变异是由遗传因素造成的，其中大部分是由母体基因组造成的。方法 我们分别对 68,732 名和 98,370 名欧洲母亲的妊娠持续时间和自发性早产进行了全基因组荟萃分析。结果荟萃分析检测到 15 个与妊娠持续时间相关的基因座，以及 4 个与早产相关的基因座。七个相关基因座是新颖的。这些位点映射到几个生物学上合理的基因，例如 HAND2，其表达在妊娠期间减少（与妊娠持续时间相关），以及 GC（维生素 D 结合蛋白），与早产相关。下游的计算机分析表明，调节作用是相关基因座的潜在机制。LD 评分回归发现出生体重指标是相关性最强的特征，凸显了自发性早产表型的独特性。组织表达和共定位分析表明生殖组织和免疫细胞类型是最相关的作用位点。结论 我们报告了与早产或妊娠持续时间相关的新遗传风险位点，并重现了之前全基因组关联研究的结果。总而言之，我们的研究结果为早产的遗传背景提供了新的见解。更好地描述因果遗传机制对公共卫生非常重要，因为它可以提出治疗和预防早产的新策略。