Twin studies traditionally have been used to assess the relative contributions of genetic and environmental factors. Nearly all common diseases and traits have now been found to be heritable and GWA studies are discovering many novel genes. However 95% of the heritability is not yet identified and discordances within identical (MZ) twin pairs cannot be explained by known environmental factors. The missing heritability could be due to epigenetic factors- which are ideally studied with twins. The proposed study uses MZ twins discordant for 10 important age-related complex disease traits to uncover epigenetic signals that are associated with disease. We will study in detail epigenetic differences using a high throughput Illumina methylation array in the 5% most discordant pairs for the following disease susceptibility traits : obesity (BMI), type II diabetes (insulin resistance) , hypertension (BP), hyperlipidemia (lipid levels), Osteoporosis (BMD), biological aging (white cell telomere levels), Allergy (IgE) , asthma (FEV1), platelet volume (MPV) and smoking. We will use the TwinsUK cohort of 3000 phenotyped MZ twins for a discovery group. For replication of the most significant associations we will use singletons from the 200 extreme highs and lows of the remaining 4000 phenotyped twins as a ‘case’-‘control ‘association study genotyped by the same array. A sub-sample will be genotyped by sequencing. To assess tissue specificity, additional tissues for methylation analysis will be sampled (buccal, fat and skin DNA). Causality will be explored using bioinformatics, cell specificity experiments and longitudinal studies using DNA stored for up to 15 years- as well as parental and offspring DNA. Epigenomics is a major future growth area. This large scale study would enable us to maintain a European lead and act also a valuable future epidemiologic resource and enable important collaborations with other European researchers and cohorts.