DNA methylation differences at growth related genes correlate with birth weight: a molecular signature linked to developmental origins of adult disease?

Abstract

BackgroundInfant birth weight is a complex quantitative trait associated with both neonatal and long-term health outcomes. Numerous studies have been published in which candidate genes (IGF1, IGF2, IGF2R, IGF binding proteins, PHLDA2 and PLAGL1) have been associated with birth weight, but these studies are difficult to reproduce in man and large cohort studies are needed due to the large inter individual variance in transcription levels. Also, very little of the trait variance is explained. We decided to identify additional candidates without regard for what is known about the genes. We hypothesize that DNA methylation differences between individuals can serve as markers of gene "expression potential" at growth related genes throughout development and that these differences may correlate with birth weight better than single time point measures of gene expression.MethodsWe performed DNA methylation and transcript profiling on cord blood and placenta from newborns. We then used novel computational approaches to identify genes correlated with birth weight.ResultsWe identified 23 genes whose methylation levels explain 70-87% of the variance in birth weight. Six of these (ANGPT4, APOE, CDK2, GRB10, OSBPL5 and REG1B) are associated with growth phenotypes in human or mouse models. Gene expression profiling explained a much smaller fraction of variance in birth weight than did DNA methylation. We further show that two genes, the transcriptional repressor MSX1 and the growth factor receptor adaptor protein GRB10, are correlated with transcriptional control of at least seven genes reported to be involved in fetal or placental growth, suggesting that we have identified important networks in growth control. GRB10 methylation is also correlated with genes involved in reactive oxygen species signaling, stress signaling and oxygen sensing and more recent data implicate GRB10 in insulin signaling.ConclusionsSingle time point measurements of gene expression may reflect many factors unrelated to birth weight, while inter-individual differences in DNA methylation may represent a "molecular fossil record" of differences in birth weight-related gene expression. Finding these "unexpected" pathways may tell us something about the long-term association between low birth weight and adult disease, as well as which genes may be susceptible to environmental effects. These findings increase our understanding of the molecular mechanisms involved in human development and disease progression.

Gestational diabetes mellitus epigenetically affects genes predominantly involved in metabolic diseases

“…significantly correlated with newborn weight (P < 0.01), Msh homeobox 1(MSX1) was the only one which was previously found to be associated with birth weight or fetal growth 38 (Table S3). It is worth noting that GDM-induced DNA methylation changes will very likely affect the infants' risk of developing obesity and type 2 diabetes later in life without affecting their birth weight.…”

Maternal adversities during pregnancy and cord blood oxytocin receptor (OXTR) DNA methylation

“…Then, each maternal predictor of adversity (ILE, EPDS, TICS-K, salivary CAR and DAY AUCg and AUCi at T2 and T3) was analysed in a separate model to avoid model over-fitting. In order to obtain information about possible confounders or mediators in the association between maternal predictors and DNA methylation, we examined sociodemographic data, pregnancy characteristics and birth outcome (see Questionnaires section) (Schlinzig et al, 2009;Hoyo et al, 2012;Turan et al, 2012). To assess the effect of a specific predictor we used the Log-likelihood-Ratio (L-Ratio) test, comparing the mixed model including the respective predictor with the corresponding model excluding it.…”

Adaptations of placental and cord bloodABCA1 DNA methylation profile to maternal metabolic status

“…They have been associated with risk factors (birth weight, child body mass index [BMI] and adiposity) known to trigger an increased long-term susceptibility to metabolic disorders. [15][16][17][18][19] The newborn epigenetic signature acquired in the womb also appears to be persistent throughout adult life in animal models and in human epidemiological studies. [20][21][22] Previously, a study carried on by Tobi et al 22 has reported that DNA methylation levels at the ATP-binding cassette transporter A1 (ABCA1) gene locus are higher in leukocytes of adults exposed prenatally to the ending World War II Dutch famine, suggesting that the ABCA1 DNA methylation profile might be sensitive to in utero adverse environmental exposure.…”