N Engl J Med 2017 09 6;377(12):1156-1167. Epub 2017 Sep 6.
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) or an association with suggestive significance (P<1.0×10) 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.).