Pregnancy and infancy are critical periods for nutritional programming of metabolic health. Epigenetic changes such as DNA methylation seem to have a crucial role linking early-life nutrition to metabolic health across the life course. The aim of NutriPROGRAM is to identify early-life nutrition-related factors and related epigenetic pathways leading to metabolic adaptations and disease across the life course.

So far, NutriPROGRAM partners have found associations of DNA methylation levels at over 900 sites in cord blood with birth weight and at almost 9000 sites with gestational age. Also, we have described DNA methylation trajectories from birth into adolescence and have created a publicly available website through which these can be visualized. In addition, a publicly available catalogue of blood autosomal cis-eQTMs in children was created. Both of these resources will help in designing and interpreting future DNA methylation studies.We have also extensively examined DNA methylation in relation to child and adolescent body mass index (BMI) and have found only minimal associations, which may indicate that DNA methylation differences are mostly a consequence rather than a cause of obesity, but this needs further study. Ongoing work focuses on further characterizing the associations of multiple nutritional exposures in pregnancy, infancy and childhood with child DNA methylation, as well as on associations of DNA methylation with cardiometabolic outcomes and a number of methodological projects. 

We expect that NutriPROGRAM will:

1) Create a set of harmonised and integrated nutrition-related factors that can be used by scientists studying the relationships between nutrition and health;

2) Lead to a better understanding of the role of DNA methylation in the pathways underlying the relation of early-life nutrition and metabolic health;

3) Lead to a better understanding of causality and modification of DNA methylation in these pathways. This will be a starting point for prevention of obesity, blood lipid disorders and type 2 diabetes;

4) Contribute to the development of methods to help identify the most promising findings from DNA methylation studies for further research;

5) Form a sustainable, international network of researchers on early-life nutrition, epigenetics and long-term metabolic outcomes that will lay the foundation for further research in this area for many years to come.

Associations of DNA methylation with birth weight

Birthweight is associated with health outcomes across the life course. DNA methylation may be an underlying mechanism. In a large meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts, including three NutriPROGRAM partners, in collaboration with the Pregnancy And Childhood Epigenetics Consortium, we found that DNA methylation in neonatal blood is associated with birthweight at 914 sites. The difference in birthweight ranged from -183 to 178 grams per 10% increase in methylation. Birthweight-related DNA methylation sites partly overlapped with some DNA methylation sites that were previously reported to be related to maternal smoking and to maternal body mass index in pregnancy, but not with those related to folate levels in pregnancy. Whether these associations are causal or explained by other factors influencing DNA methylation requires further research.

Trajectories of DNA methylation from birth to adolescence

DNA methylation is known to play an important role in chid health and development, but not much is known about how DNA methylation changes with age in this important period of life. Using information from over 2300 children, we have characterized trajectories of DNA methylation from birth into adolescence. We found that DNA methylation changes with age at over half of the examined CpG sites and that there are differences between individuals in terms of patterns of change. These findings support a developmental role for DNA methylation and will be important for future studies in this area. We have created a publicly available website where the DNA methylation trajectories can be visualized: http://epidelta.mrcieu.ac.uk.

DNA methylation in relation to gene expression

For the biological interpretation of studies on DNA methylation, it is important to understand the associations of DNA methylation and gene expression. In over 800 children, we charcterized these associations. We found 63,831 cis-eQTMs, expression quantitative trait methylation, defined as correlations between gene expression and DNA methylation levels, representing 35,228 unique CpGs and 11,071 genes (transcript clusters). The overlap of child blood cis-eQTMs with those previously described in adults was small. Only half of the cis-eQTMs could be captured through annotation to the closest gene. This catalogue of blood autosomal cis-eQTMs in children can help the biological interpretation of EWAS findings. It is publicly available at: https://helixomics.isglobal.org/. 

DNA methylation and body mass index from birth to adolescence

DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using data from up to 4133 children from 23 studies. Overall, there were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across chidlhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adults BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity, but this needs further study.

Paternal body mass index and child DNA methylation

Previous small, mostly candidate gene studies have shown associations between paternal pre-pregnancy body mass index (BMI) and offspring-blood DNA methylation. In NutriPROGRAM and the Pregnancy and Childhood Epigenetics (PACE) consortium, we co-ordinated epigenome-wide association studies of paternal BMI in relation to DNA methylation and then meta-analysed the results across 13 data sets at birth (4894 babies) and six data sets in childhood (1982 babies). We found little evidence to support previous findings, even at imprinted regions. However, this does not rule out the possibility of a paternal epigenetic effect in different tissues, at regions not covered by the 450k array, via different mechanisms or in populations with greater extremes of paternal BMI. More research is warranted to help in understanding the size and nature of contributions of paternal adiposity to offspring epigenetics and health outcomes.