Abstract
The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10−14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.
Highlights
The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors
We found that conditioning on maternal genotype did not attenuate the fetal genetic association while the maternal genetic association conditional on fetal genotype was non-significant (Table 2). These results indicate that the association signal for gestational duration at the 2q13 locus represents a fetal genetic effect
We used the genome-wide association studies (GWAS) Catalog[33] to identify 39 SNPs known from previous studies to be associated with cytokine levels and examined associations for these SNPs with gestational duration in our discovery stage meta-analysis. These SNPs did not show more evidence of association with gestational duration than expected by chance (Supplementary Fig. 9). In this genome-wide meta-analysis including a total of 93,980 infants in the discovery and replication stages, we identified a fetal locus on chromosome 2q13 that was robustly associated with gestational duration
Summary
The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Compared to many other mammals, humans have a highly invasive placentation process with direct contact with the maternal circulation[1,4], and the immunological paradox of pregnancy continues to be an important research topic It is well-established that successful gestation depends on numerous mechanisms, some of which involve inflammatory pathways[5]. Postterm birth, defined as birth after a gestation of 42 completed weeks (hereafter weeks) or more is associated with increased risks of fetal and neonatal mortality and morbidity plus increased maternal morbidity[14] Each of these outcomes affects approximately 5% to 10% of all births in high income countries[15,16] and preterm birth rates are considerably higher in some low- and middle-income countries[17]. Most genome-wide association studies (GWAS) of birth timing have been limited in sample size and have not identified robustly associated genetic loci[23,24,25,26,27]
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