Genetic studies of gestational duration and preterm birth

Abstract

The fine control of birth timing is important to human survival and evolution. A key challenge in studying the mechanisms underlying the regulation of human birth timing is that human parturition is a unique to human event - animal models provide only limited information. The duration of gestation or the risk of preterm birth is a complex human trait under genetic control from both maternal and fetal genomes. Genomic discoveries through genome-wide association (GWA) studies would implicate relevant genes and pathways. Similar to other complex human traits, gestational duration is likely to be influenced by numerous genetic variants of small effect size. The detection of these small-effect genetic variants requires very large sample sizes. In addition, several practical and analytical challenges, in particular the involvement of both maternal and fetal genomes, further complicate the genetic studies of gestational duration and other pregnancy phenotypes. Despite these challenges, large-scale GWA studies have already identified several genomic loci associated with gestational duration or the risk of preterm birth. These genomic discoveries have revealed novel insights about the biology of human birth timing. Expanding genomic discoveries in larger datasets by more refined analytical approaches, together with the functional analysis of the identified genomic loci, will collectively elucidate the biological processes underlying the control of human birth timing.

Keywords: Complex human trait; Genome-wide association; Gestational duration; Preterm birth.

Fig. 1

Recurrence risks of preterm birth (PTB) (Figure courtesy of Dr. Joe Leigh Simpson). (A) Women whose first deliveries were preterm have a higher chance of PTB in their second deliveries, especially when the first deliveries had shorter gestations . (B) Mothers who themselves were born preterm have an increased risk of PTB . (C) PTBs to a woman's mother, full sisters, or maternal half-sisters increase her PTB risk, whereas PTB in her paternal half-sisters or in members of her partner's family do not affect her risk .

Fig. 2

Haplotype transmission in a duo or trio.

Fig. 3

Possible causal mechanisms that can lead to the observational associations between a maternal phenotype and pregnancy outcomes. (A) Direct causal effect (maternal effect) of maternal phenotype on pregnancy outcomes. (B) Associations of social and nutritional confounders that have impacts on both maternal phenotype and pregnancy outcomes. (C) Fetal genetics that directly influences pregnancy outcomes.

Fig. 4

Conventional (A) and integrated maternal/fetal approach (B) to gestational phenotypes.