Genetic Associations with Gestational Duration and Spontaneous Preterm Birth
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Genetic Associations with Gestational Duration and Spontaneous Preterm Birth. / 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.; Karjalainen, M. K.; Rämet, M.; Sengpiel, V.; Geller, F.; Boyd, H. A.; Palotie, A.; Momany, A.; Bedell, B.; Ryckman, K. K.; Huusko, J. M.; Forney, C. R.; Kottyan, L. C.; Hallman, M.; Teramo, K.; Nohr, E. A.; Smith, G. Davey; Melbye, M.; Jacobsson, B.; Muglia, L. J.
In: New England Journal of Medicine, Vol. 377, No. 12, 21.09.2017, p. 1156-1167.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Genetic Associations with Gestational Duration and Spontaneous Preterm Birth
AU - Zhang, G.
AU - Feenstra, B.
AU - Bacelis, J.
AU - Liu, X.
AU - Muglia, L. M.
AU - Juodakis, J.
AU - Miller, D. E.
AU - Litterman, N.
AU - Jiang, P. P.
AU - Russell, L.
AU - Hinds, D. A.
AU - Hu, Y.
AU - Weirauch, M. T.
AU - Chen, X.
AU - Chavan, A. R.
AU - Wagner, G. P.
AU - Pavličev, M.
AU - Nnamani, M. C.
AU - Maziarz, J.
AU - Karjalainen, M. K.
AU - Rämet, M.
AU - Sengpiel, V.
AU - Geller, F.
AU - Boyd, H. A.
AU - Palotie, A.
AU - Momany, A.
AU - Bedell, B.
AU - Ryckman, K. K.
AU - Huusko, J. M.
AU - Forney, C. R.
AU - Kottyan, L. C.
AU - Hallman, M.
AU - Teramo, K.
AU - Nohr, E. A.
AU - Smith, G. Davey
AU - Melbye, M.
AU - Jacobsson, B.
AU - Muglia, L. J.
PY - 2017/9/21
Y1 - 2017/9/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85029567766&partnerID=8YFLogxK
U2 - 10.1056/NEJMoa1612665
DO - 10.1056/NEJMoa1612665
M3 - Journal article
C2 - 28877031
AN - SCOPUS:85029567766
VL - 377
SP - 1156
EP - 1167
JO - New England Journal of Medicine
JF - New England Journal of Medicine
SN - 0028-4793
IS - 12
ER -
ID: 196442537