The genomics of preterm birth: from animal models to human studies

Abstract

Preterm birth (delivery at less than 37 weeks of gestation) is the leading cause of infant mortality worldwide. So far, the application of animal models to understand human birth timing has not substantially revealed mechanisms that could be used to prevent prematurity. However, with amassing data implicating an important role for genetics in the timing of the onset of human labor, the use of modern genomic approaches, such as genome-wide association studies, rare variant analyses using whole-exome or genome sequencing, and family-based designs, holds enormous potential. Although some progress has been made in the search for causative genes and variants associated with preterm birth, the major genetic determinants remain to be identified. Here, we review insights from and limitations of animal models for understanding the physiology of parturition, recent human genetic and genomic studies to identify genes involved in preterm birth, and emerging areas that are likely to be informative in future investigations. Further advances in understanding fundamental mechanisms, and the development of preventative measures, will depend upon the acquisition of greater numbers of carefully phenotyped pregnancies, large-scale informatics approaches combining genomic information with information on environmental exposures, and new conceptual models for studying the interaction between the maternal and fetal genomes to personalize therapies for mothers and infants. Information emerging from these advances will help us to identify new biomarkers for earlier detection of preterm labor, develop more effective therapeutic agents, and/or promote prophylactic measures even before conception.

Prevention of preterm birth: Harnessing science to address the global epidemic

“…Analyses of birth timing of the offspring of twins suggest little or no contribution from the paternal genome. Consistent with this finding, segregation analysis shows that maternal genome effects in both the mother and the fetus are much more prominent than paternal effects (13). A comparison of the offspring of twins, full siblings, and half siblings estimated that 13% of the variation in gestational age at delivery was explained by fetal genetic factors, and 21% was accounted for by maternal genetic factors (14).…”

“…These observations point to the existence of genetic contributors to PTB through the maternal lineage. More formal genetic studies in offspring of twins and segregation analysis of traits in families consistently demonstrate that 30 to 40% of the variation in birth timing is due to genetic factors (13).…”

Genomics of Preterm Birth

“…There have been several recent reviews summarizing the current state of knowledge for candidate gene association studies with human preterm birth in case -control cohorts or transmission disequilibrium designs (we refer readers to these sources for detailed descriptions: Crider et al 2005; Committee on Understanding Premature Birth and Assuring Healthy Outcomes 2006;Plunkett and Muglia 2008;Bezold et al 2013). In general, compelling evidence for specific genes as substantially contributing to or protecting from preterm birth risk has not emerged.…”

Whole-Exome Sequencing and Whole-Genome Sequencing in Critically Ill Neonates Suspected to Have Single-Gene Disorders

“…In 2011, the preterm birth rate, defined as infants born before 37 wk gestation, was 11.72% in the United States (Bettegowda et al 2010). Although specific numbers are not available, it is also likely that being born prematurely is a risk factor for having a monogenic disorder and that premature birth has a strong genetic basis (Chaudhari et al 2008;Bezold et al 2013). Preterm birth results in $26 billion annual economic costs (Behrman and Butler 2007).…”