Genetic Associations with Gestational Duration and Spontaneous Preterm Birth.
Genetic Associations with Gestational Duration and Spontaneous Preterm Birth.
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DOI：
10.1056/nejmoa1612665
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发表时间：
2017-09-21
期刊：
影响因子：
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通讯作者：
Muglia LJ
中科院分区：
文献类型：
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作者：
Zhang G;Feenstra B;Bacelis J;Liu X;Muglia LM;Juodakis J;Miller DE;Litterman N;Jiang PP;Russell L;Hinds DA;Hu Y;Weirauch MT;Chen X;Chavan AR;Wagner GP;Pavličev M;Nnamani MC;Maziarz J;Karjalainen MK;Rämet M;Sengpiel V;Geller F;Boyd HA;Palotie A;Momany A;Bedell B;Ryckman KK;Huusko JM;Forney CR;Kottyan LC;Hallman M;Teramo K;Nohr EA;Davey Smith G;Melbye M;Jacobsson B;Muglia LJ
Despite evidence that genetic factors contribute to gestational length and preterm birth, robust associations with genetic variants have not been identified. We hypothesized that analyzing larger data sets with gestational length information by genomewide association would reveal trait-influencing variants. We performed a genomewide association study in a discovery data set of 43,568 women of European ancestry from 23andMe, Inc., for gestational length as a continuous trait and for term or preterm (<37 weeks) birth as a dichotomous outcome. We used three Nordic data sets (8,643 women) for replication of 14 genomic loci achieving either genomewide (P < 5×10-8) or suggestive association (P < 1×10-6). In the discovery stage, for gestational length, four loci (EBF1, EEFSEC, AGTR2 and WNT4) achieved genomewide significance, all of which were replicated in the Nordic data sets. Functional analysis of the WNT4 locus indicated the likely causative variant alters the binding of ESR1. ADCY5 and RAP2C, which had suggestive significance in the discovery stage, were significantly replicated and achieved genomewide significance in joint analysis. Common variants in EBF1, EEFSEC and AGTR2 were also associated with preterm birth with genomewide significance. Analysis of mother-infant dyads indicated that these findings likely resulted from maternal genome actions. Our study is the first to identify maternal genetic variants robustly associated with gestational length and preterm birth. Roles of these loci in uterine development, maternal nutrition, and vascular control support their mechanistic involvement and create opportunities to investigate new risk factors for prevention of preterm birth.
