AIMS

The proposed project aims to investigate the relationship between increased risk of type 2 diabetes and methylation profile. Specifically:

1. Is variation in DNA methylation associated with risk of type 2 diabetes?

In ALSPAC mothers, individuals will be selected based on high and low risk of developing type 2 diabetes (using measures of glucose and insulin, metabolomics data, diagnoses of gestational diabetes or repeated measures of glycosuria during pregnancy). We will then look for associated patterns of DNA methylation.

2. Can DNA methylation signatures predict who progresses to type 2 diabetes and/or other co-morbidities (cardiovascular disease) from those who will not?

Using follow-up data from ALSPAC mothers (FOM) we will investigate if methylation status at baseline has any predictive influence on which individuals developed adverse health outcomes (type 2 diabetes or worsened metabolic profile). DNA methylation measures at follow-up will identify methylation differences over time and may also identify loci associated with later health adversity.

3. How do genetic variation influence methylation patterns?

At methylation loci of interest (following discovery in aims 1&2) we will identify any relationship between methylation and measured genetic variants. This will help us to understand by how much methylation patterns are determined by the underlying genetic sequence.

4. To utilise genetic sequence-methylation associations in order to distinguish between non-causal biomarkers and causal pathways

The causal/non-causal relationships between genotype, DNA methylation and metabolic measures will be investigated using Mendelian randomisation. Using genotype information from objective 3, SNPs that correlate highly with methylation at CpG sites of interest will be utilised as 'proxy' measures of DNA methylation. This permits the use of genotype data and therefore the relationship between (proxy) methylation and outcome of interest can be evaluated.