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妊娠时长和自发性早产的遗传关联
Genetic Associations with Gestational Duration and Spontaneous Preterm Birth


Ge Zhang ... 妇产科和儿科 • 2017.09.21

摘要


背景

尽管有证据表明遗传因素对妊娠时长和早产风险有影响,但与遗传变异的可靠关联尚未确定。在本研究中,我们应用了包含妊娠时长的大数据集来确定可能的遗传关联。

 

方法

我们进行了一项全基因组关联研究,发现阶段的样本集来自43,568名欧洲裔女性,并以妊娠时长为连续性状,以足月产或早产(不足37周)为二分类结局。我们采用来自三个北欧数据集的样本(共包含8,643名女性)来验证在发现阶段数据集中具有显著全基因组关联(P<5.0×10−8)和提示性显著关联(P<1.0×10−6)的基因座。

 

结果

在发现和验证阶段数据集中,四个基因座(EBF1EEFSECAGTR2WNT4)与妊娠时长显著相关。功能分析表明WNT4的一种相关变异改变了雌激素受体的结合。ADCY5RAP2C的变异与妊娠时长在发现阶段数据集中有提示性显著关联,在验证阶段数据集中有显著关联;这些变异在联合分析中也显示出全基因组显著关联。EBF1EEFSECAGTR2的常见变异与早产有全基因组显著关联。母婴成对(mother-infant dyad)分析提示这些变异在母体基因组水平起作用。

 

结论

在这项全基因组关联研究中,我们发现EBF1EEFSECAGTR2WNT4ADCY5RAP2C基因座的变异与妊娠时长相关。EBF1EEFSECAGTR2基因座的变异与早产相关。既往确定的这些基因在子宫发育、母体营养和血管控制等方面的作用支持在机制上的相关性(由美国出生缺陷基金会[March of Dimes]等资助)。





作者信息

Ge Zhang, M.D., Ph.D., Bjarke Feenstra, Ph.D., Jonas Bacelis, B.S., Xueping Liu, Ph.D., Lisa M. Muglia, Ph.D., Julius Juodakis, B.S., Daniel E. Miller, B.S., Nadia Litterman, Ph.D., Pan-Pan Jiang, Ph.D., Laura Russell, M.S., David A. Hinds, Ph.D., Youna Hu, Ph.D., Matthew T. Weirauch, Ph.D., Xiaoting Chen, Ph.D., Arun R. Chavan, M.Sci., Günter P. Wagner, Ph.D., Mihaela Pavličev, Ph.D., Mauris C. Nnamani, Ph.D., Jamie Maziarz, M.Sc., Minna K. Karjalainen, Ph.D., Mika Rämet, M.D., Ph.D., Verena Sengpiel, M.D., Ph.D., Frank Geller, M.Sc., Heather A. Boyd, Ph.D., Aarno Palotie, M.D., Ph.D., Allison Momany, B.S., Bruce Bedell, M.A., Kelli K. Ryckman, Ph.D., Johanna M. Huusko, Ph.D., Carmy R. Forney, B.S., Leah C. Kottyan, Ph.D., Mikko Hallman, M.D., Ph.D., Kari Teramo, M.D., Ph.D., Ellen A. Nohr, Ph.D., George Davey Smith, D.Sc., Mads Melbye, M.D., D.M.Sc., Bo Jacobsson, M.D., Ph.D., and Louis J. Muglia, M.D., Ph.D.
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.). Address reprint requests to Dr. Muglia at Cincinnati Children’s Hospital Medical Center, MLC 7009, 3333 Burnet Ave., Cincinnati, OH 45229-3026, or at louis.muglia@cchmc.org.

 

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