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Abstract
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Candidate Gene Analysis in Preterm Birth
Conclusions/Future Opportunities
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Genetics of preterm birth

Profile image of Mihaela PavlicevMihaela Pavlicev
https://doi.org/10.1002/9780470015902.A0025448
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Abstract

The control of normal birth timing in mammals and the fundamental signals that initiate preterm birth in humans are critical areas of scientific investigation. Preterm birth is the leading cause of infant mortality throughout the world, and the single greatest challenge in women's and children's health today. Despite the recognised importance of this area of investigation, relatively limited advances have been made. In part, this limited success in revealing mechanisms results from divergence in the endocrine physiology of pregnancy between species. To have an effect on these biological and medical gaps in knowledge, new genetic studies in humans and comparative genomic investigations across species have been undertaken. In this article, the authors summarise the current status of genetic and genomic approaches to elucidate the control of birth timing.

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Endocrine Reviews, 2000

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Genetic Associations with Gestational Duration and Spontaneous Preterm Birth
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BACKGROUND Despite 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. METHODS We 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. RESULTS In 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. CONCLUSIONS In this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and variants at the EBF1, EEFSEC, and AGTR2 loci with preterm birth. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control support their mechanistic involvement. (Funded by the March of Dimes and others.

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Human Heredity, 2009

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Cold Spring Harbor perspectives in medicine, 2015

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Genetic effects on the timing of parturition and links to fetal birth weight
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The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n = 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (cases = 18,797, controls = 260,246) revealed 6 associated loci, and large genetic similarities with gestational duration. Analysis of the parental transmitted and non-transmitted alleles (n = 136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, while seven act both through the maternal and fetal, and two act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight.

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Mother’s Genome or Maternally-Inherited Genes Acting in the Fetus Influence Gestational Age in Familial Preterm Birth
Adrienne Stormo

Human Heredity, 2009

to birth timing since sporadic (i.e. no familial resemblance) and nontransmission (i.e. environmental factors alone contribute to gestational age) models are strongly rejected. Analyses of gestational age attributed to the infant support a model in which mother's genome and/or maternally-inherited genes acting in the fetus are largely responsible for birth timing, with a smaller contribution from the paternallyinherited alleles in the fetal genome. Conclusion: Our findings suggest that genetic influences on birth timing are important and likely complex.

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Inherited Predisposition to Spontaneous Preterm Delivery
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LEVEL OF EVIDENCE: II P reterm birth is the leading cause of perinatal morbidity and mortality 1 in the developed world, costing society $26 billion per year. 2 It accounts for 60% of deaths in babies and serious complications after delivery, 3 such as cerebral palsy. Spontaneous preterm birth refers to any delivery between 24 and 37 weeks of gestation in the absence of induced labor or elective cesarean delivery, 4 and it occurs in 7% of all deliveries in the United Kingdom. 5 Elsewhere, including the United States, it has been reported in 12% to 13% of all births, 6,7 representing an increase of 30% since 1981. A recent analysis of Scottish national See related editorial on page 1114.

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Human evolution, genomics and birth timing: new approaches for investigating preterm birth
Mihaela Pavlicev

and Pavlicev have disclosed no financial relationships relevant to this article. Dr Muglia has disclosed that work reported in this article was supported by grants from the National Institutes of Health and the March of Dimes. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/ device.

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Genomics of preterm birth
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The molecular mechanisms controlling human birth timing at term, or resulting in preterm birth, have been the focus of considerable investigation, but limited insights have been gained over the past 50 years. In part, these processes have remained elusive because of divergence in reproductive strategies and physiology shown by model organisms, making extrapolation to humans uncertain. Here, we summarize the evolution of progesterone signaling and variation in pregnancy maintenance and termination. We use this comparative physiology to support the hypothesis that selective pressure on genomic loci involved in the timing of parturition have shaped human birth timing, and that these loci can be identified with comparative genomic strategies. Previous limitations imposed by divergence of mechanisms provide an important new opportunity to elucidate fundamental pathways of parturition control through increasing availability of sequenced genomes and associated reproductive physiology chara...

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An Evolutionary Genomic Approach to Identify Genes Involved in Human Birth Timing
Louis Muglia

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Coordination of fetal maturation with birth timing is essential for mammalian reproduction. In humans, preterm birth is a disorder of profound global health significance. The signals initiating parturition in humans have remained elusive, due to divergence in physiological mechanisms between humans and model organisms typically studied. Because of relatively large human head size and narrow birth canal cross-sectional area compared to other primates, we hypothesized that genes involved in parturition would display accelerated evolution along the human and/or higher primate phylogenetic lineages to decrease the length of gestation and promote delivery of a smaller fetus that transits the birth canal more readily. Further, we tested whether current variation in such accelerated genes contributes to preterm birth risk. Evidence from allometric scaling of gestational age suggests human gestation has been shortened relative to other primates. Consistent with our hypothesis, many genes involved in reproduction show human acceleration in their coding or adjacent noncoding regions. We screened .8,400 SNPs in 150 human accelerated genes in 165 Finnish preterm and 163 control mothers for association with preterm birth. In this cohort, the most significant association was in FSHR, and 8 of the 10 most significant SNPs were in this gene. Further evidence for association of a linkage disequilibrium block of SNPs in FSHR, rs11686474, rs11680730, rs12473870, and rs1247381 was found in African Americans. By considering human acceleration, we identified a novel gene that may be associated with preterm birth, FSHR. We anticipate other human accelerated genes will similarly be associated with preterm birth risk and elucidate essential pathways for human parturition.

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The high rate of preterm birth in the USA and many other countries is a potential target for improving children&#39;s immediate health and reducing the medical problems they face as adults. The acute complications for infants born prematurely often require intensive care management and are followed by long-lasting cognitive, sensory, motor, and cardiovascular deficits that substantially limit adult capabilities and survival. The inability to effectively reduce preterm birth stems from the failure to understand normal mechanisms of parturition in humans. Although studies from several model organisms help define the physiology of maintenance and termination of pregnancy, there are fundamental differences between species. For example, species regulate their production of progesterone, the crucial hormone in sustaining pregnancy, differently. This limits the extent to which models can provide meaningful information about the physiological mechanisms of human gestation. The growing wealt...

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