Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age

Abstract

Background Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods We performed meta-analysis of Illumina’s HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4–18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results We identified 8899 CpGs in cord blood that were associated with gestational age (range 27–42 weeks), at Bonferroni significance, P < 1.06 × 10− 7, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.

Prenatal Exposure to Per- and Polyfluoroalkyl Substances, Umbilical Cord Blood DNA Methylation, and Cardio-Metabolic Indicators in Newborns: The Healthy Start Study

“…Reported sex of the infant was compared with predicted sex and participants were excluded if the reported and predicted sex did not match (n = 6). Extreme methylation outliers were removed by trimming M-values for each probe more than three times the interquartile range below the 25th percentile or above the 75th percentile (Hoaglin et al 1986;Merid et al 2020).…”

Epigenome Wide Association and Stochastic Epigenetic Mutation Analysis on Cord Blood of Preterm Birth

“…Epigenetics is considered a term of connection between genetics and environment and for this reason recently became a natural field of investigation in PTB and DNA methylation, in particular, representing the most studied epigenetic modification. Recent findings in cord blood, identified more than 8800 CpG sites associated with gestational age and the pathway analyses identified enrichment for biological processes critical to embryonic development of brain and lung tissue [ 10 ]. Moreover, several studies analyzed cord blood DNA methylation levels comparing preterm and full-term babies and reported a great number of significant differences even if the consistence among these studies has not been evaluated yet [ 11 , 12 , 13 , 14 , 15 ].…”

Identification of methylation changes associated with positive and negative growth deviance in Gambian infants using a targeted methyl sequencing approach of genomic DNA

“…The probability that these matches have occurred by chance for 62 and 11 genes is 0.19 −62 and 0.029 −11 , respectively. Comparisons have been made to two further studies examining the impact of gestational age 86 (where some of the data are subsumed in the large meta-analysis mentioned above) and smoking on birthweight 87 ; these share, respectively, 53 (marked with a green asterisk in Table S2a-d) and 11 (marked with a blue asterisk) genes associated with differential methylation identified in the current study. These two studies identify a further 22 DMR-associated genes that overlap with our findings, bringing the replication in other related studies to 84 (48%) of the 173 implicated genes we have documented (The asterisks in figure 2 and 3 mark which of those shared genes show 5% or greater methylation change-in total 49 of the 93 in tables 5 and 6 between the three birthweight-related studies).…”