Higher birth order is associated with altered risk of many disease states. Changes in placentation and exposures to in utero growth factors with successive pregnancies may impact later life disease risk via persistent DNA methylation alterations. We investigated birth order with Illumina DNA methylation array data in each of 16 birth cohorts (8164 newborns) with European, African, and Latino ancestries from the Pregnancy and Childhood Epigenetics Consortium. Meta-analyzed data demonstrated systematic DNA methylation variation in 341 CpGs (FDR adjusted P < 0.05) and 1107 regions. Forty CpGs were located within known quantitative trait loci for gene expression traits in blood, and trait enrichment analysis suggested a strong association with immune-related, transcriptional control, and blood pressure regulation phenotypes. Decreasing fertility rates worldwide with the concomitant increased proportion of first-born children highlights a potential reflection of birth order-related epigenomic states on changing disease incidence trends.

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.

The 2014-2016 JET results are reviewed in the light of their significance for optimising the ITER research plan for the active and non-active operation. More than 60 h of plasma operation with ITER first wall materials successfully took place since its installation in 2011. New multi-machine scaling of the type I-ELM divertor energy flux density to ITER is supported by first principle modelling. ITER relevant disruption experiments and first principle modelling are reported with a set of three disruption mitigation valves mimicking the ITER setup. Insights of the L-H power threshold in Deuterium and Hydrogen are given, stressing the importance of the magnetic configurations and the recent measurements of fine-scale structures in the edge radial electric. Dimensionless scans of the core and pedestal confinement provide new information to elucidate the importance of the first wall material on the fusion performance. H-mode plasmas at ITER triangularity (H = 1 at β N ∼ 1.8 and n/n GW ∼ 0.6) have been sustained at 2 MA during 5 s. The ITER neutronics codes have been validated on high performance experiments. Prospects for the coming D-T campaign and 14 MeV neutron calibration strategy are reviewed.