Genetic Associations with Gestational Duration and Spontaneous Preterm Birth.,The New England Journal of Medicine

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Genetic Associations with Gestational Duration and Spontaneous Preterm Birth.
The New England Journal of Medicine ( IF 96.2 ) Pub Date : 2017-09-06 , DOI: 10.1056/nejmoa1612665
Ge Zhang ₁ , Bjarke Feenstra ₁ , Jonas Bacelis ₁ , Xueping Liu ₁ , Lisa M Muglia ₁ , Julius Juodakis ₁ , Daniel E Miller ₁ , Nadia Litterman ₁ , Pan-Pan Jiang ₁ , Laura Russell ₁ , David A Hinds ₁ , Youna Hu ₁ , Matthew T Weirauch ₁ , Xiaoting Chen ₁ , Arun R Chavan ₁ , Günter P Wagner ₁ , Mihaela Pavličev ₁ , Mauris C Nnamani ₁ , Jamie Maziarz ₁ , Minna K Karjalainen ₁ , Mika Rämet ₁ , Verena Sengpiel ₁ , Frank Geller ₁ , Heather A Boyd ₁ , Aarno Palotie ₁ , Allison Momany ₁ , Bruce Bedell ₁ , Kelli K Ryckman ₁ , Johanna M Huusko ₁ , Carmy R Forney ₁ , Leah C Kottyan ₁ , Mikko Hallman ₁ , Kari Teramo ₁ , Ellen A Nohr ₁ , George Davey Smith ₁ , Mads Melbye ₁ , Bo Jacobsson ₁ , Louis J Muglia ₁

Affiliation

From the Division of Human Genetics (G.Z., L.J.M.), Center for Autoimmune Genomics and Etiology (M.T.W., D.E.M., X.C., C.R.F., L.C.K.) and the Divisions of Biomedical Informatics and Developmental Biology (M.T.W.), Cincinnati Children's Hospital Medical Center, and the Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children's Hospital Medical Center and March of Dimes Prematurity Research Center Ohio Collaborative (G.Z., L.M.M., M.P., J.M.H., L.J.M.), Cincinnati; the Department of Epidemiology Research, Statens Serum Institut (B.F., X.L., F.G., H.A.B., M.M.), and the Department of Clinical Medicine, University of Copenhagen (M.M.), Copenhagen, and the Research Unit of Gynecology and Obstetrics, Institute of Clinical Research, University of Southern Denmark, Odense (E.A.N.) - all in Denmark; the Department of Obstetrics and Gynecology, Sahlgrenska University Hospital Östra (J.B., V.S.), the Department of Obstetrics and Gynecology, Institute of Clinical Sciences (J.J.), and the Department of Obstetrics and Gynecology (B.J.), Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 23andMe, Mountain View (N.L., P.-P.J., L.R., D.A.H., Y.H.), and the Department of Medicine, Stanford University School of Medicine, Stanford (M.M.) - both in California; the Department of Ecology and Evolutionary Biology, Yale University (A.R.C., G.P.W., M.C.N., J.M.), and the Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale Medical School (G.P.W.), New Haven, and the Yale Systems Biology Institute, West Haven (A.R.C., G.P.W., M.C.N., J.M.) - all in Connecticut; the Department of Obstetrics and Gynecology, Wayne State University, Detroit (G.P.W.); the PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu, and the Department of Children and Adolescents, Oulu University Hospital, Oulu (M.K.K., M.R., J.M.H., M.H.), and the Institute for Molecular Medicine Finland, University of Helsinki (A.P.), and Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital (K.T.), Helsinki - all in Finland; the Analytic and Translational Genetics Unit, Department of Medicine, the Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, and the Department of Neurology, Massachusetts General Hospital, Boston (A.P.), and the Program in Medical and Population Genetics and the Stanley Center for Psychiatric Research, Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge (A.P.) - both in Massachusetts; the Departments of Pediatrics (A.M., B.B.) and Epidemiology (K.K.R.), College of Public Health, and the Department of Pediatrics (K.K.R.), Carver College of Medicine, University of Iowa, Iowa City; the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom (G.D.S.); and the Department of Genetics and Bioinformatics, Area of Health Data and Digitalization, Norwegian Institute of Public Health, Oslo (B.J.).

BACKGROUND Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations. METHODS We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (<37 weeks) birth as a dichotomous outcome. We used samples from three Nordic data sets (involving a total of 8643 women) to test for replication of genomic loci that had significant genomewide association (P<5.0×10-8) or an association with suggestive significance (P<1.0×10-6) in the discovery set. RESULTS In the discovery and replication data sets, four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. Functional analysis showed that an implicated variant in WNT4 alters the binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets; these variants also showed genomewide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genomewide significance. An analysis of mother-infant dyads suggested that these variants act at the level of the maternal genome. CONCLUSIONS In this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and variants at the EBF1, EEFSEC, and AGTR2 loci with preterm birth. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control support their mechanistic involvement. (Funded by the March of Dimes and others.).

中文翻译：

与妊娠期和自然早产的遗传关联。

背景尽管有证据表明遗传因素会影响妊娠持续时间和早产风险，但尚未确定与遗传变异的强关联。我们使用包含妊娠期的大型数据集来确定可能的遗传关联。方法我们在从 43,568 名欧洲血统女性获得的一组发现样本中进行了全基因组关联研究，使用妊娠持续时间作为连续特征，将足月或早产（<37 周）作为二分结果。我们使用来自三个北欧数据集（共涉及 8643 名女性）的样本来测试具有显着全基因组关联（P<5.0×10-8）或具有暗示意义的关联（P<1.0×10-8）的基因组位点的复制。 6）在发现集中。结果在发现和复制数据集中，四个基因座（EBF1、EEFSEC、AGTR2 和 WNT4）与妊娠持续时间显着相关。功能分析表明，WNT4 中的一个相关变体改变了雌激素受体的结合。ADCY5 和 RAP2C 的变异与妊娠期之间的关联在发现集中具有暗示意义，在复制集中具有关联的重要证据；这些变体在联合分析中也显示出全基因组意义。EBF1、EEFSEC 和 AGTR2 中的常见变异与早产相关，具有全基因组意义。对母婴二元组的分析表明，这些变异在母体基因组水平上起作用。结论在这项全基因组关联研究中，我们发现 EBF1、EEFSEC、AGTR2、WNT4、ADCY5、和 RAP2C 基因座与早产的 EBF1、EEFSEC 和 AGTR2 基因座的妊娠持续时间和变异相关。先前确定的这些基因在子宫发育、母体营养和血管控制中的作用支持它们的机械参与。（由一角钱三月和其他人资助。）。

更新日期：2017-09-20

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