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Genetic associations with gestational duration and spontaneous preterm birth

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.; Smith, George Davey; Melbye, Mads; Jacobsson, Bo; Muglia, Louis J. (2017-09-06)

 
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URL:
https://doi.org/10.1056/NEJMoa1612665

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.
Smith, George Davey
Melbye, Mads
Jacobsson, Bo
Muglia, Louis J.
Massachusetts Medical Society
06.09.2017

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

https://rightsstatements.org/vocab/InC/1.0/
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.
https://rightsstatements.org/vocab/InC/1.0/
doi:https://doi.org/10.1056/NEJMoa1612665
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https://urn.fi/URN:NBN:fi-fe201709288780
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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. (Funded by the March of Dimes and others.)

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