University of Oulu

Zhang, G., Feenstra, B., Bacelis, J., Liu, X., Muglia, L., Juodakis, J., Miller, D., Litterman, N., Jiang, P., Russell, L., Hinds, D., Hu, Y., Weirauch, M., Chen, X., Chavan, A., Wagner, G., Pavličev, M., Nnamani, M., Maziarz, J., Karjalainen, M., Rämet, M., Sengpiel, V., Geller, F., Boyd, H., Palotie, A., Momany, A., Bedell, B., Ryckman, K., Huusko, J., Forney, C., Kottyan, L., Hallman, M., Teramo, K., Nohr, E., Davey Smith, G., Melbye, M., Jacobsson, B., Muglia, L. (2017) Genetic Associations with Gestational Duration and Spontaneous Preterm Birth. New England Journal of Medicine, 377 (12), 1156-1167. doi:10.1056/NEJMoa1612665

Genetic associations with gestational duration and spontaneous preterm birth

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Author: Zhang, Ge1,2; Feenstra, Bjarke3; Bacelis, Jonas4;
Organizations: 1Division of Human Genetics, Cincinnati Children’s Hospital Medical Center
2Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical Center and March of Dimes Prematurity Research Center Ohio Collaborative
3Department of Epidemiology Research, Statens Serum Institut
4Department of Obstetrics and Gynecology, Sahlgrenska University Hospital Östra
5Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg
6Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center
8Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children’s Hospital Medical Center
9Department of Ecology and Evolutionary Biology, Yale University
10Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale Medical School
11Department of Obstetrics and Gynecology, Wayne State University
12PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu
13Department of Children and Adolescents, Oulu University Hospital
14Institute for Molecular Medicine Finland, University of Helsinki
15Analytic and Translational Genetics Unit, Department of Medicine, the Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, and the Department of Neurology, Massachusetts General Hospital
16Program in Medical and Population Genetics and the Stanley Center for Psychiatric Research, Broad Institute of the Massachusetts Institute of Technology and Harvard
17Department of Pediatrics, College of Public Health
18Department of Epidemiology, College of Public Health
19Department of Pediatrics, Carver College of Medicine, University of Iowa
20Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital
21Research Unit of Gynecology and Obstetrics, Institute of Clinical Research, University of Southern Denmark
22Medical Research Council Integrative Epidemiology Unit at the University of Bristol, School of Social and Community Medicine, University of Bristol
23Department of Clinical Medicine, University of Copenhagen
24Department of Medicine, Stanford University School of Medicine
25Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg
26Department of Genetics and Bioinformatics, Area of Health Data and Digitalization, Norwegian Institute of Public Health
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.5 MB)
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Language: English
Published: Massachusetts Medical Society, 2017
Publish Date: 2018-03-06


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.)

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Series: New England journal of medicine
ISSN: 0028-4793
ISSN-E: 1533-4406
ISSN-L: 0028-4793
Volume: 377
Issue: 12
Pages: 1156 - 1167
DOI: 10.1056/NEJMoa1612665
Type of Publication: A1 Journal article – refereed
Field of Science: 3123 Gynaecology and paediatrics
Funding: Supported by grants (22-FY15-003, to Dr. Muglia; and 21-FY16-121) from the March of Dimes, grants from the National Institutes of Health, grants (to Drs. Jiang, Hu, Hinds, and Litterman and Ms. Russell) from the Cincinnati Children’s Hospital Medical Center, a grant (to Dr. Muglia) from the Fifth Third Foundation, a grant (OPP1113966, to Dr. Muglia) from the Bill and Melinda Gates Foundation, a grant from the Jane and Aatos Erkko Foundation, grants (FUGE 183220/S10 and FRIMEDKLI-05 ES236011) from the Norwegian Research Council, a grant from the Jane and Dan Olsson Foundations, a grant (ALFGBG-507701) from the Swedish government to researchers in the public health service, and a grant (FP7/2007-2013) from the European Community’s Seventh Framework Program (grant agreement HEALTH-F4-2007-201413). Dr. Wagner is supported by a grant (54860) from the John Templeton Foundation; Dr. Feenstra, by an Oak Foundation fellowship; Dr. Liu, by the Nordic Center of Excellence in Health-Related e-Sciences; the Norwegian Mother and Child Cohort Study, by the Norwegian Ministry of Health and the Ministry of Education and Research, by the National Institute of Environmental Health Sciences (contract no. N01-ES-75558), the National Institute of Neurological Disorders and Stroke (UO1 NS 047537-01 and UO1 NS 047537-06A1), by the Norwegian Research Council/FUGE (151918/S10 and FRI-MEDBIO 249779), and by the Swedish Research Council (2015-02559); Dr. Palotie, by the Academy of Finland; Dr. Ryckman, by the March of Dimes, Bill and Melinda Gates Foundation, and National Institutes of Health; Dr. Chavan and Ms. Maziarz, by the John Templeton Foundation; and Dr. Boyd, by the National Institutes of Health Genes, Environment, and Health Initiative and the Danish Council for Independent Research, Medical Sciences. Support from the Functional Genomics Core at Cincinnati Children’s Hospital Medical Center was made possible through a grant (P30 AR070549) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
Copyright information: From Zhang, G., et al. (2017) Genetic Associations with Gestational Duration and Spontaneous Preterm Birth. New England Journal of Medicine, 377 (12), 1156-1167. Copyright © 2017 Massachusetts Medical Society. Reprinted with permission.