Jevon Plunkett

Genetic contributions to preterm birth: Implications from epidemiological and genetic association studies

Infants born before term (<37 weeks) have an increased risk of neonatal mortality as well as other health problems. The increasing rate of preterm birth in recent decades, despite improvements in health care, creates an impetus to better understand and prevent this disorder. Preterm birth likely depends on a number of interacting factors, including genetic, epigenetic, and environmental risk factors. Genetic studies may identify markers, which more accurately predict preterm birth than currently known risk factors, or novel proteins and/or pathways involved in the disorder. This review summarizes epidemiological and genetic studies to date, emphasizing the complexity of genetic influences on birth timing. While several candidate genes have been reportedly associated with the disorder, inconsistency across studies has been problematic. More systematic and unbiased genetic approaches are needed for future studies to examine the genetic etiology of human birth timing thoroughly.

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

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.

Heritability of parturition timing: an extended twin design analysis.

OBJECTIVE The objective of the study was to assess relative maternal and paternal genetic influences on birth timing. STUDY DESIGN Utilizing The Netherlands Twin Registry, we examined the correlation in birth timing of infants born to monozygotic (MZ) twins and their first-degree relatives (dizygotic twins and siblings of twins). Genetic models estimated the relative influence of genetic and common environmental factors through model fitting of additive genetic (A), common environmental (C), individual-specific environmental factors, and combinations thereof. RESULTS We evaluated birth timing correlation among the infants of 1390 twins and their 644 siblings. The correlation in MZ female twins (r = 0.330) was greater than MZ male twins (r = -0.096). Positive correlation were also found in sister-sister pairs (r = 0.223) but not in brother-brother (r = -0.045) or brother-sister pairs (r = -0.038). The most parsimonious AE model indicated a significant maternal contribution of genetic and individual-specific environmental factors to birth timing, but no paternal heritability was demonstrated. Heritability of birth timing in women was 34%; and the remaining variance (66%) was caused by individual-specific environmental factors. CONCLUSION Our data implicate a significant contribution of maternal but not paternal genetic influences on birth timing.

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

Objective: While multiple lines of evidence suggest the importance of genetic contributors to risk of preterm birth, the nature of the genetic component has not been identified. We perform segregation analyses to identify the best fitting genetic model for gestational age, a quantitative proxy for preterm birth. Methods: Because either mother or infant can be considered the proband from a preterm delivery and there is evidence to suggest that genetic factors in either one or both may influence the trait, we performed segregation analysis for gestational age either attributed to the infant (infant’s gestational age), or the mother (by averaging the gestational ages at which her children were delivered), using 96 multiplex preterm families. Results: These data lend further support to a genetic component contributing 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 paternally-inherited alleles in the fetal genome. Conclusion: Our findings suggest that genetic influences on birth timing are important and likely complex.

The Genetics of Birth Timing: Insights into a Fundamental Component of Human Development

The timing of birth necessitates the coupling of fetal maturation with the onset of parturition, and occurs at characteristic, but divergent gestations between mammals. Preterm birth in humans is an important but poorly understood outcome of pregnancy that uncouples fetal maturation and birth timing. The etiology of preterm birth is complex, involving environmental and genetic factors whose underlying molecular and cellular pathogenic mechanisms remain poorly understood. Animal models, although limited by differences with human physiology, have been crucial in exploring the role of various genetic pathways in mammalian birth timing. Studies in humans of both familial aggregation and racial disparities in preterm birth have contributed to the understanding that preterm birth is heritable. A significant portion of this heritability is due to polygenic causes with few true Mendelian disorders contributing to preterm birth. Thus far, studies of the human genetics of preterm birth using a candidate gene approach have met with limited success. Emerging research efforts using unbiased methods may yield promising results if concerns about study design can be adequately addressed. The findings from this frontier of research may have direct implications for the allocation of public health and clinical resources as well as spur the development of more effective therapeutics.

Population-based estimate of sibling risk for preterm birth, preterm premature rupture of membranes, placental abruption and pre-eclampsia

BackgroundAdverse pregnancy outcomes, such as preterm birth, preeclampsia and placental abruption, are common, with acute and long-term complications for both the mother and infant. Etiologies underlying such adverse outcomes are not well understood. As maternal and fetal genetic factors may influence these outcomes, we estimated the magnitude of familial aggregation as one index of possible heritable contributions.Using the Missouri Department of Healths maternally-linked birth certificate database, we performed a retrospective population-based cohort study of births (1989–1997), designating an individual born from an affected pregnancy as the proband for each outcome studied. We estimated the increased risk to siblings compared to the population risk, using the sibling risk ratio, λs, and sibling-sibling odds ratio (sib-sib OR), for the adverse pregnancy outcomes of preterm birth, preterm premature rupture of membranes (PPROM), placental abruption, and pre-eclampsia.ResultsRisk to siblings of an affected individual was elevated above the population prevalence of a given disorder, as indicated by λS (λS (95% CI): 4.3 (4.0–4.6), 8.2 (6.5–9.9), 4.0 (2.6–5.3), and 4.5 (4.4–4.8), for preterm birth, PPROM, placental abruption, and pre-eclampsia, respectively). Risk to siblings of an affected individual was similarly elevated above that of siblings of unaffected individuals, as indicated by the sib-sib OR (sib-sib OR adjusted for known risk factors (95% CI): 4.2 (3.9–4.5), 9.6 (7.6–12.2), 3.8 (2.6–5.5), 8.1 (7.5–8.8) for preterm birth, PPROM, placental abruption, and pre-eclampsia, respectively).ConclusionThese results suggest that the adverse pregnancy outcomes of preterm birth, PPROM, placental abruption, and pre-eclampsia aggregate in families, which may be explained in part by genetics.

A Potential Novel Spontaneous Preterm Birth Gene, AR, Identified by Linkage and Association Analysis of X Chromosomal Markers

Preterm birth is the major cause of neonatal mortality and morbidity. In many cases, it has severe life-long consequences for the health and neurological development of the newborn child. More than 50% of all preterm births are spontaneous, and currently there is no effective prevention. Several studies suggest that genetic factors play a role in spontaneous preterm birth (SPTB). However, its genetic background is insufficiently characterized. The aim of the present study was to perform a linkage analysis of X chromosomal markers in SPTB in large northern Finnish families with recurrent SPTBs. We found a significant linkage signal (HLOD  = 3.72) on chromosome locus Xq13.1 when the studied phenotype was being born preterm. There were no significant linkage signals when the studied phenotype was giving preterm deliveries. Two functional candidate genes, those encoding the androgen receptor (AR) and the interleukin-2 receptor gamma subunit (IL2RG), located near this locus were analyzed as candidates for SPTB in subsequent case-control association analyses. Nine single-nucleotide polymorphisms (SNPs) within these genes and an AR exon-1 CAG repeat, which was previously demonstrated to be functionally significant, were analyzed in mothers with preterm delivery (n = 272) and their offspring (n = 269), and in mothers with exclusively term deliveries (n = 201) and their offspring (n = 199), all originating from northern Finland. A replication study population consisting of individuals born preterm (n = 111) and term (n = 197) from southern Finland was also analyzed. Long AR CAG repeats (≥26) were overrepresented and short repeats (≤19) underrepresented in individuals born preterm compared to those born at term. Thus, our linkage and association results emphasize the role of the fetal genome in genetic predisposition to SPTB and implicate AR as a potential novel fetal susceptibility gene for SPTB.

Sequence variants in oxytocin pathway genes and preterm birth: a candidate gene association study

BackgroundPreterm birth (PTB) is a complex disorder associated with significant neonatal mortality and morbidity and long-term adverse health consequences. Multiple lines of evidence suggest that genetic factors play an important role in its etiology. This study was designed to identify genetic variation associated with PTB in oxytocin pathway genes whose role in parturition is well known.MethodsTo identify common genetic variants predisposing to PTB, we genotyped 16 single nucleotide polymorphisms (SNPs) in the oxytocin (OXT), oxytocin receptor (OXTR), and leucyl/cystinyl aminopeptidase (LNPEP) genes in 651 case infants from the U.S. and one or both of their parents. In addition, we examined the role of rare genetic variation in susceptibility to PTB by conducting direct sequence analysis of OXTR in 1394 cases and 1112 controls from the U.S., Argentina, Denmark, and Finland. This study was further extended to maternal triads (maternal grandparents-mother of a case infant, N=309). We also performed in vitro analysis of selected rare OXTR missense variants to evaluate their functional importance.ResultsMaternal genetic effect analysis of the SNP genotype data revealed four SNPs in LNPEP that show significant association with prematurity. In our case–control sequence analysis, we detected fourteen coding variants in exon 3 of OXTR, all but four of which were found in cases only. Of the fourteen variants, three were previously unreported novel rare variants. When the sequence data from the maternal triads were analyzed using the transmission disequilibrium test, two common missense SNPs (rs4686302 and rs237902) in OXTR showed suggestive association for three gestational age subgroups. In vitro functional assays showed a significant difference in ligand binding between wild-type and two mutant receptors.ConclusionsOur study suggests an association between maternal common polymorphisms in LNPEP and susceptibility to PTB. Maternal OXTR missense SNPs rs4686302 and rs237902 may have gestational age-dependent effects on prematurity. Most of the OXTR rare variants identified do not appear to significantly contribute to the risk of PTB, but those shown to affect receptor function in our in vitro study warrant further investigation. Future studies with larger sample sizes are needed to confirm the findings of this study.

Fine-Mapping an Association of FSHR with Preterm Birth in a Finnish Population

Preterm birth is a complex disorder defined by gestations of less than 37 weeks. While preterm birth is estimated to have a significant genetic component, relative few genes have been associated with preterm birth. Polymorphism in one such gene, follicle-stimulating hormone receptor (FSHR), has been associated with preterm birth in Finnish and African American mothers but not other populations. To refine the genetic association of FSHR with preterm birth we conducted a fine-mapping study at the FSHR locus in a Finnish cohort. We sequenced a total of 44 kb, including protein-coding and conserved non-coding regions, in 127 preterm and 135 term mothers. Overall, we identified 288 single nucleotide variants and 65 insertion/deletions of 1–2 bp across all subjects. While no common SNPs in protein-coding regions were associated with preterm birth, including one previously associated with timing of fertilization, multiple SNPs spanning the first and second intron showed the strongest associations. Analysis of the associated SNPs revealed that they form both a protective (OR = 0.50, 95% CI = 0.25–0.93) as well as a risk (OR = 1.89, 95% CI = 1.08–3.39) haplotype with independent effects. In these haplotypes, two SNPs, rs12052281 and rs72822025, were predicted to disrupt ZEB1 and ELF3 transcription factor binding sites, respectively. Our results show that multiple haplotypes at FSHR are associated with preterm birth and we discuss the frequency and structure of these haplotypes outside of the Finnish population as a potential explanation for the absence of FSHR associations in some populations.

Primate-specific evolution of noncoding element insertion into PLA2G4C and human preterm birth.

BackgroundThe onset of birth in humans, like other apes, differs from non-primate mammals in its endocrine physiology. We hypothesize that higher primate-specific gene evolution may lead to these differences and target genes involved in human preterm birth, an area of global health significance.MethodsWe performed a comparative genomics screen of highly conserved noncoding elements and identified PLA2G4C, a phospholipase A isoform involved in prostaglandin biosynthesis as human accelerated. To examine whether this gene demonstrating primate-specific evolution was associated with birth timing, we genotyped and analyzed 8 common single nucleotide polymorphisms (SNPs) in PLA2G4C in US Hispanic (n = 73 preterm, 292 control), US White (n = 147 preterm, 157 control) and US Black (n = 79 preterm, 166 control) mothers.ResultsDetailed structural and phylogenic analysis of PLA2G4C suggested a short genomic element within the gene duplicated from a paralogous highly conserved element on chromosome 1 specifically in primates. SNPs rs8110925 and rs2307276 in US Hispanics and rs11564620 in US Whites were significant after correcting for multiple tests (p < 0.006). Additionally, rs11564620 (Thr360Pro) was associated with increased metabolite levels of the prostaglandin thromboxane in healthy individuals (p = 0.02), suggesting this variant may affect PLA2G4C activity.ConclusionsOur findings suggest that variation in PLA2G4C may influence preterm birth risk by increasing levels of prostaglandins, which are known to regulate labor.