The aim of the proposed programme of work is to establish the role of epigenetic mechanisms (DNA methylation) in the developmental programming of disease in later life. This will involve establishing both the determinants of epigenetic variation (i.e. the relationship between various exposures and methylation status in DNA at available time points) and the consequences of epigenetic varaition (i.e. the relationship between DNA methylation status and phenotypic outcomes).

In addition, the transmission of epigenetic patterns from mother to child will be investigated. The role of maternal epigenetic signatures in determining child epigenotype and phenotype will be explored.

A further area of interest is the role of common genetic variation in dictating epigenetic patterns. Using existing ALSPAC genotype data will we be able to explore whether genotype (both maternal and child) impacts upon epigenetic variation. When epigenotype is considered a a phenotype, a Mendelian randomisation approach can be used to explore the determinants of epigenetic status.

This work will be pursued via a varity of funding opportunities including the following;

1. ERC Programme Grant: "Epigenetic Epidemiology; the role of epigenetic variation in common complex disease". 2 million euro, submitted Dec 2008, outcome July 2009.

2. Biomedical Research Centre in Ageing, Newcastle University: "DNA methylation and ageing". £60K, submitted Feb 2009, outcome April 2009.

3. MRC Project grant: "Epigenetic mechanisms in the developmental programming of obesity". For submission May 2009.

4. Wellcome Trust; "A comparative study of epigenetic variation in low and middle income country settings with a UK adolescent birth cohort". For submission July 2009.

Studies will involve array-based approaches to define gene loci that demonstarte epigenentic variation (MeDIP-chip, Illumina BeadArray probable platforms) in a small sub-set of samples (typically 24 paired; exposed/unexposed, case/control or 2 extremes of phenotype) followed by quantatitive DNA methylation (qCpG) analysis of specific loci in a substantial number of samples (n=1000+). qCpG analysis will be undertaken using Pyrosequencing or Sequenom MassArray. A candidate gene-based approach utilising qCpG without requiring array analysis is also feasible.

DNA requirements for microarray are 1ug at 100ng/ul. For subsequent qCpG analysis the same quantity is required to analyse 5-10 loci.

Data will be required on a range of exposures and phenotypes at serail timepoints and in both children and mothers. An outline description of the data required is provided below;

Phenotypes of multiple outcomes that show evidence of developmental programming including; obesity and related traits, cardiovascular disease and related traits in children from the ALSPAC cohort; Pre- and postnatal exposures which may plausibly influence programming including maternal smoking and nutritional variables and maternal and child genotypes that can be used as instrumental variables (e.g. MTHFR) ; other prenatal exposures and socio-demographic variables. DNA methylation profiles of children linked to phenotype and exposure data.