BackgroundDespite evidence that genetic factors contribute to gestational length and preterm birth, robust associations with genetic variants have not been identified. We hypothesized that analyzing larger data sets with gestational length information by genomewide association would reveal trait-influencing variants.MethodsWe performed a genomewide association study in a discovery data set of 43,568 women of European ancestry from 23andMe, Inc., for gestational length as a continuous trait and for term or preterm (<37 weeks) birth as a dichotomous outcome. We used three Nordic data sets (8,643 women) for replication of 14 genomic loci achieving either genomewide (P < 5×10-8) or suggestive association (P < 1×10-6).ResultsIn the discovery stage, for gestational length, four loci (EBF1, EEFSEC, AGTR2 and WNT4) achieved genomewide significance, all of which were replicated in the Nordic data sets. Functional analysis of the WNT4 locus indicated the likely causative variant alters the binding of ESR1. ADCY5 and RAP2C, which had suggestive significance in the discovery stage, were significantly replicated and achieved genomewide significance in joint analysis. Common variants in EBF1, EEFSEC and AGTR2 were also associated with preterm birth with genomewide significance. Analysis of mother-infant dyads indicated that these findings likely resulted from maternal genome actions.ConclusionsOur study is the first to identify maternal genetic variants robustly associated with gestational length and preterm birth. Roles of these loci in uterine development, maternal nutrition, and vascular control support their mechanistic involvement and create opportunities to investigate new risk factors for prevention of preterm birth.

BACKGROUNDDespite 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. METHODSWe 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. RESULTSIn 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. CONCLUSIONSIn this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and

We identified SPOCK2 as a new possible candidate susceptibility gene for bronchopulmonary dysplasia. Its lung expression pattern points toward a potential role in alveolarization.