Zhang Ge, Feenstra Bjarke, Bacelis Jonas, Liu Xueping, Muglia Lisa M, Juodakis Julius, Miller Daniel E, Litterman Nadia, Jiang Pan-Pan, Russell Laura, Hinds David A, Hu Youna, Weirauch Matthew T, Chen Xiaoting, Chavan Arun R, Wagner Günter P, Pavličev Mihaela, Nnamani Mauris C, Maziarz Jamie, Karjalainen Minna K, Rämet Mika, Sengpiel Verena, Geller Frank, Boyd Heather A, Palotie Aarno, Momany Allison, Bedell Bruce, Ryckman Kelli K, Huusko Johanna M, Forney Carmy R, Kottyan Leah C, Hallman Mikko, Teramo Kari, Nohr Ellen A, Davey Smith George, Melbye Mads, Jacobsson Bo, Muglia Louis J
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.).
N Engl J Med. 2017 Sep 21;377(12):1156-1167. doi: 10.1056/NEJMoa1612665. Epub 2017 Sep 6.
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.
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) or an association with suggestive significance (P<1.0×10) in the discovery set.
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.
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.).
尽管有证据表明遗传因素会影响妊娠期长短和早产风险，但尚未确定与基因变异的有力关联。我们使用包含妊娠期长短的大型数据集来确定可能的遗传关联。
我们对从43568名欧洲血统女性中获取的样本进行了全基因组关联研究，将妊娠期长短作为连续性状，足月或早产（<37周）分娩作为二分结局。我们使用来自三个北欧数据集（共涉及8643名女性）的样本，对在发现集中具有全基因组显著关联（P<5.0×10）或提示性显著关联（P<1.0×10）的基因组位点进行重复检验。
在发现集和重复数据集中，四个位点（EBF1、EEFSEC、AGTR2和WNT4）与妊娠期长短显著相关。功能分析表明，WNT4中一个相关变异改变了雌激素受体的结合。ADCY5和RAP2C中的变异与妊娠期长短的关联在发现集中具有提示性显著意义，在重复数据集中具有显著关联证据；这些变异在联合分析中也显示出全基因组显著意义。EBF1、EEFSEC和AGTR2中的常见变异与早产具有全基因组显著关联。母婴二元组分析表明，这些变异在母本基因组水平起作用。
在这项全基因组关联研究中，我们发现EBF1、EEFSEC、AGTR2、WNT4、ADCY5和RAP2C位点的变异与妊娠期长短相关，EBF1、EEFSEC和AGTR2位点的变异与早产相关。这些基因先前在子宫发育、母体营养和血管控制中的作用支持了它们在机制上的参与。（由美国疾病控制与预防中心等资助。）
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