Obesity and its related metabolic disorders represent a major social, economic and health burden.

There is immense interest in epigenetic processes and the role that they might play in mediating

complex disease risk through their influence on gene regulation. This project adopts an

epidemiological approach, including the development of novel data analysis methods, and aims to

further our understanding of the contribution made by epigenetic mechanisms to obesity and its

sequelae, including non alcoholic fatty liver disease.

This study will measure DNA methylation patterns in children at birth and at age 15 and relate

these to a wide array of exposures and obesity-related traits, and importantly, the trajectory of

these traits. It represents by far the largest study of DNA methylation and its association with

obesity-related exposures (beginning in utero) and outcomes to date. The study will utilise a world

leading longitudinal study which has followed children from birth to age 17 (with future follow-up

planned) and has amassed an unprecedented amount of data on these individuals. To

complement large, well-powered human epidemiological studies of peripheral blood DNA

methylation, analysis of tissue specific DNA methylation will be analysed in human biopsy samples

and both DNA methylation and gene expression will be analysed in a range of target tissues in

animal models.

The study will identify obesity-related DNA methylation patterns using the Illumina 450k human

methylation array in 250 children at birth and age 15. From these data a custom panel of

methylation sites associated with obesity-related exposures and the phenotype itself will be

designed. A total of 1,200 children will then be analysed to establish the relationship between

methylation variation and obesity and its associated metabolic disorders. In addition the

association of DNA methylation signatures with common genetic variation will be investigated and

data analysis techniques developed to strengthen causal inference. Finally tissue specific

methylation patterns will be explored using human liver tissue and multiple tissues from animal

models of obesity.

The study will make a significant contribution to the emerging field of epigenetic epidemiology and

the data arising will be made available to the wider scientific community.