Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration

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.

Haplotype-based analysis distinguishes maternal-fetal genetic contribution to pregnancy-related outcomes

“…Heritability estimation based on epidemiological studies suggest that fetal genetic factors contribute 11-35% and 27-42% of variation in gestational duration and fetal growth measures at birth respectively whereas maternal genetic factors contribute 13-20% and 19-22% of variation in gestational duration and fetal growth measures at birth [52][53][54][55][56][57][58] respectively. Similar patterns of maternal and fetal genetic contributions to the variance of pregnancy phenotypes are observed through genetic studies using GRMs based on an individual's genotypes 21,23,27,28,30,41,48,59,60 .…”

Protein Concentrations of Thrombospondin-1, MIP-1β, and S100A8 Suggest the Reflection of a Pregnancy Clock in Mid-Trimester Amniotic Fluid

“…In genetic studies, analyzing gestational duration has proven more successful than dichotomizing this trait, suggesting that a single biological pathway common to all preterm cases is unlikely to be identified [9,33]. Several of the examined proteins in our study were associated with gestational duration, but these associations appeared to be driven by the term delivery group rather than the spontaneous PTD group.…”

Contribution of de novo and inherited rare CNVs to very preterm birth

“…In summary, preterm birth is a growing public health problem with implications across the life span. However, there have only been a small number of investigations of rare genetic variants,13–15 22 with most studies showing inconsistent results without adequate power. Our findings suggest that the rate of de novo CNVs, especially rare pathogenic variants, could be elevated in those born very preterm.…”

“…A large maternal genome-wide association study (GWAS) of gestational age at delivery (n=43 568 mothers),13 which included 3331 women who self-reported preterm birth (<37 weeks), identified six maternal loci to be significantly associated with gestational age and three with preterm birth. A more recent fetal GWAS meta-analysis identified one locus on chromosome 2q13 to be associated with gestational duration, although no locus reached genome-wide significance for preterm birth as a dichotomous outcome 14. Huusko et al 15 reported that rare variants in glucocorticoid receptor signalling pathway were common to ten Finnish mothers with recurrent spontaneous preterm births.…”