Localization of a major susceptibility locus influencing preterm birth

Chittoor, Geetha; Farook, Vidya S.; Puppala, Sobha; Fowler, Sharon P.; Schneider, Jennifer L.; Dyer, Thomas D.; Cole, Shelley A.; Lynch, Jane; Curran, Joanne E.; Almasy, Laura; MacCluer, Jean W.; Comuzzie, Anthony G.; Hale, Daniel E.; Ramamurthy, Rajam S.; Dudley, Donald J.; Moses, Eric K.; Arya, Rector; Lehman, Donna M.; Jenkinson, Christopher P.; Bradshaw, Ben; DeFronzo, Ralph A.; Blangero, John; Duggirala, Ravindranath

doi:10.1093/molehr/gat036

Cited by 7 publications

(9 citation statements)

References 97 publications

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“…Our first goal was to confirm our previous report of widespread changes in EOPE ( 19 ) and then to test for similar changes in LOPE and nIUGR using the same approach. We chose less stringent cutoffs for significance in this analysis (FDR < 0.05 & Δβ > 0.1) as compared with Blair et al (2013) (FDR < 0.01 & Δβ > 0.125) ( 19 ) as our aim was to identify a larger number of differentially methylated sites that could be used for further validation. Based on these criteria, a total of 1703 sites were differentially methylated between EOPE and pre-term controls ( Fig.…”

Section: Resultsmentioning

confidence: 89%

“…We previously showed widespread DNAm alterations in EOPE ( 19 ) using the Illumina Infinium HumanMethylation450 Array (450K), measuring >480 000 CpG sites across the genome ( 20 ). We also demonstrated that placentas associated with confined placental trisomy 16, a condition that can be associated with PE, show some overlapping changes with chromosomally normal EOPE, as well as a unique set of changes specific to the presence of the trisomy ( 21 ).…”

Section: Introductionmentioning

confidence: 99%

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Mining DNA methylation alterations towards a classification of placental pathologies

Wilson

Leavey

Cox

et al. 2017

Human Molecular Genetics

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Placental health is a key component to a successful pregnancy. Placental insufficiency (PI), inadequate nutrient delivery to the fetus, is associated with preeclampsia (PE), a maternal hypertensive disorder, and intrauterine growth restriction (IUGR), pathologically poor fetal growth. PI is more common in early-onset PE (EOPE) than late-onset PE (LOPE). However, the relationship between these disorders remains unclear. While DNA methylation (DNAm) alterations have been identified in PE and IUGR, these entities can overlap and few studies have analysed them separately. This study aims to utilize DNAm profiling to better understand the underlying placental variation associated with PE and IUGR. Placental samples from a discovery (43 controls, 22 EOPE, 18 LOPE, 11 IUGR) and validation cohort (15 controls, 22 EOPE, 11 LOPE) were evaluated using the Illumina HumanMethylation450 array. To account for gestational age (GA) effects, EOPE samples were compared with pre-term births of varying etiologies (GA <37 weeks). LOPE and IUGR were compared with term controls (GA >37 weeks). While 1703 sites were differentially methylated (DM) (FDR < 0.05, Δβ > 0.1) in EOPE, few changes were associated with LOPE (N = 5), or IUGR (N = 0). Of the 1703 EOPE sites, 599 validated in the second cohort. Using these 599 sites, both cohorts clustered into three distinct groups. Interestingly, LOPE samples diagnosed between 34 and 36 weeks with co-occurring IUGR clustered with the EOPE. DNAm profiling may provide an independent tool to refine clinical/pathological diagnoses into subgroups with more uniform pathology. Despite large changes observed in EOPE, there were challenges in reproducing genome-wide DNAm hits that are discussed.

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Section: Resultsmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Mining DNA methylation alterations towards a classification of placental pathologies

Wilson

Leavey

Cox

et al. 2017

Human Molecular Genetics

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“…Fetal growth increasing the tension in the uterine wall, increased oxytocin and estrogen bioactivity, progesterone withdrawal and inflammatory decidual activation, all contribute to the initiation of contractions [ 3 , 5 ]. For several populations susceptibility loci influencing preterm birth have been reported, but until now this has not resulted in the identification of additional general mechanisms involved in preterm labor [ 6 – 9 ]. It is currently not known if there are other fetal properties, apart from fetal growth, that relate to the premature onset of delivery.…”

Section: Introductionmentioning

confidence: 99%

The idiopathic preterm delivery methylation profile in umbilical cord blood DNA

et al. 2015

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BackgroundPreterm delivery is the leading cause of neonatal morbidity and mortality. Two-thirds of preterm deliveries are idiopathic. The initiating molecular mechanisms behind spontaneous preterm delivery are unclear. Umbilical cord blood DNA samples are an easy source of material to study the neonatal state at birth. DNA methylation changes can be exploited as markers to identify spontaneous preterm delivery. To identify methylation differences specific to idiopathic preterm delivery, we assessed genome-wide DNA methylation changes in 24 umbilical cord blood samples (UCB) using the 450 K Illumina methylation array. After quality control, conclusions were based on 11 term and 11 idiopathic preterm born neonates. The differentially methylated positions (DMPs) specific for preterm/term delivery, neonatal sex, use of oxytocin and mode of initiation of labor were calculated by controlling the FDR p value at 0.05.ResultsThe analysis identifies 1855 statistically significant DMPs between preterm and term deliveries of which 508 DMPs are also attributable to clinical variables other than preterm versus term delivery.1347 DMPs are unique to term vs preterm delivery, of which 196 DMPs do not relate to gestational age as such. Pathway analysis indicated enrichment of genes involved in calcium signalling, myometrial contraction and relaxation pathways. The 1151 DMPs that correlate with advancing gestational age (p < 0.05) include 161 DMPs that match with two previously reported studies on UCB methylation.Additionally, 123 neonatal sex specific DMPs, 97 DMPs specific to the induction of labour and 42 DMPs specific to the mode of initiation of labor were also identified.ConclusionThis study identifies 196 DMPs in UCB DNA of neonates which do not relate to gestational age or any other clinical variable recorded and are specific to idiopathic preterm delivery. Furthermore, 161 DMPs from our study overlap with previously reported studies of which a subset is also reported to be differentially methylated at 18 years of age. A DMP on MYL4, encoding myosin light chain 4, is a robust candidate for the identification of idiopathic preterm labour as it is identified by all 3 independent studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1915-4) contains supplementary material, which is available to authorized users.

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“…A study by Chittoor et al . examined the susceptibility of Mexican Americans to PTB using a linkage analysis across 1,439 individuals and found a significant linkage signal for a region on chromosome 18 containing 52 potential candidate genes 42 . Whole exome sequencing of a limited set of maternal genomes from European families revealed an over-representation of rare variants in the complement/coagulation factor cascade 43 .…”

Section: Introductionmentioning

confidence: 99%

A genome-wide association study identifies only two ancestry specific variants associated with spontaneous preterm birth

Rappoport

Toung

Hadley

et al. 2018

Sci Rep

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Preterm birth (PTB), or the delivery prior to 37 weeks of gestation, is a significant cause of infant morbidity and mortality. Although twin studies estimate that maternal genetic contributions account for approximately 30% of the incidence of PTB, and other studies reported fetal gene polymorphism association, to date no consistent associations have been identified. In this study, we performed the largest reported genome-wide association study analysis on 1,349 cases of PTB and 12,595 ancestry-matched controls from the focusing on genomic fetal signals. We tested over 2 million single nucleotide polymorphisms (SNPs) for associations with PTB across five subpopulations: African (AFR), the Americas (AMR), European, South Asian, and East Asian. We identified only two intergenic loci associated with PTB at a genome-wide level of significance: rs17591250 (P = 4.55E-09) on chromosome 1 in the AFR population and rs1979081 (P = 3.72E-08) on chromosome 8 in the AMR group. We have queried several existing replication cohorts and found no support of these associations. We conclude that the fetal genetic contribution to PTB is unlikely due to single common genetic variant, but could be explained by interactions of multiple common variants, or of rare variants affected by environmental influences, all not detectable using a GWAS alone.

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Localization of a major susceptibility locus influencing preterm birth

Cited by 7 publications

References 97 publications

Mining DNA methylation alterations towards a classification of placental pathologies

Mining DNA methylation alterations towards a classification of placental pathologies

The idiopathic preterm delivery methylation profile in umbilical cord blood DNA

A genome-wide association study identifies only two ancestry specific variants associated with spontaneous preterm birth

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