Genetic Associations with Gestational Duration and Spontaneous Preterm Birth

Ge Zhang, Bjarke Feenstra, Jonas Bacelis, Xueping Liu, Lisa M Muglia, Julius Juodakis, Daniel E Miller, Nadia Litterman, Pan-Pan Jiang, Laura Russell, David A Hinds, Youna Hu, Matthew T Weirauch, Xiaoting Chen, Arun R Chavan, Günter P Wagner, Mihaela Pavličev, Mauris C Nnamani, Jamie Maziarz, Minna K KarjalainenMika Rämet, Verena Sengpiel, Frank Geller, Heather A Boyd, Aarno Palotie, Allison Momany, Bruce Bedell, Kelli K Ryckman, Johanna M Huusko, Carmy R Forney, Leah C Kottyan, Mikko Hallman, Kari Teramo, Ellen A Nohr, George Davey Smith, Mads Melbye, Bo Jacobsson, Louis J Muglia

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Abstract

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.

Original languageEnglish
JournalThe New England Journal of Medicine
Volume377
Issue number12
Pages (from-to)1156-1167
ISSN0028-4793
DOIs
Publication statusPublished - 21. Sep 2017

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Keywords

  • Adenylyl Cyclases/genetics
  • Datasets as Topic
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Genome-Wide Association Study
  • Gestational Age
  • Humans
  • Peptide Elongation Factors/genetics
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Pregnancy
  • Premature Birth/genetics
  • Receptor, Angiotensin, Type 2/genetics
  • Regression Analysis
  • Trans-Activators/genetics
  • Wnt4 Protein/genetics
  • ras Proteins/genetics

Cite this

Zhang, G., Feenstra, B., Bacelis, J., Liu, X., Muglia, L. M., Juodakis, J., Miller, D. E., Litterman, N., Jiang, P-P., Russell, L., Hinds, D. A., Hu, Y., Weirauch, M. T., Chen, X., Chavan, A. R., Wagner, G. P., Pavličev, M., Nnamani, M. C., Maziarz, J., ... Muglia, L. J. (2017). Genetic Associations with Gestational Duration and Spontaneous Preterm Birth. The New England Journal of Medicine, 377(12), 1156-1167. https://doi.org/10.1056/NEJMoa1612665