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Genetic Associations With Gestational Duration and Spontaneous Preterm Birth
Journal article   Open access   Peer reviewed

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, …
Obstetrical & gynecological survey, Vol.73(2), pp.83-85
02/01/2018
DOI: 10.1097/01.ogx.0000530434.15441.45
url
https://europepmc.org/articles/pmc5561422View
Published (Version of record) Open Access

Abstract

Preterm birth, caused by idiopathic onset of uterine contractions or rupture of fetal membranes, is a major risk factor for death in neonates and children younger than 5 years. Although there is evidence that preterm birth and gestational duration are affected by both maternal and fetal genomes, robust associations with genetic variations are still not established. This 2-stage Genomewide Association Study (GWAS) aimed to determine genetic associations with gestational duration (preterm, <37 weeks; term, >= 37 weeks) and risk of preterm birth. Genomewide discovery data were obtained from a cohort of women of European ancestry (43,568) and identified associations were tested for replication in 3 Nordic data sets (8643). Women in the discovery data set were participants in the research program of 23andMe, and DNA extraction and genotyping were performed by the National Genetics Institute. Statistical analysis was performed, and loci with suggestive influence (P < 1.0 x 10(-6)) were tested in the replication stage. An association was considered to be replicated if the P value of the most strongly associated single-nucleotide polymorphism was less than the threshold of significance and had a combined discovery and replication P < 5.0 x 10(-8). The discovery and replication data sets showed that EBF1, EEFSEC, AGTR2, and WNT4 were strongly linked with gestational duration. It was noted through a functional analysis that an implicated variant in WNT4 changes the binding of estrogen receptor 1 (ESR1). Furthermore, variants in ADCY5 and RAP2C were found to be associated with gestational duration and had significant presence in the discovery set. The ADCY5 and RAP2C variants also exhibited a strong association in replication sets and genomewide significance in a joint analysis. EBF1, EEFSEC, and AGTR2 variants were significantly associated with both preterm birth and gestational duration. A joint association analysis in mother-infant pairs showed significant associations only with maternal genotypes and not with fetal genotypes, indicating a maternal origin of these genetic associations. This GWAS revealed the benefits of using a large sample of self-reported phenotyping combined with a smaller but more precisely phenotyped replication cohort to locate maternal loci associated with gestational duration and pretermbirth. Variants located at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were robustly associated with gestational duration, and variants at the EBF1, EEFSEC, and AGTR2 loci showed genome-wide significance with preterm birth.
 Life Sciences & Biomedicine Obstetrics & Gynecology Science & Technology

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