Final Report Summary - EPITWIN (The role of epigenetic factors in the aetiology of common complex diseases using twins)
Twin studies have traditionally been used to assess the relative contributions of genetic and environmental factors to human complex traits, and these now offer an opportunity to study epigenetic variation as a dynamic quantitative trait. High monozygotic twin discordance rates for common diseases suggest that unexplained environmental or epigenetic factors could be involved. The EpiTwin project (http://www.epitrain.eu/) aimed to explore this hypothesis by profiling the epigenomes of 5,000 twins, using a combination of DNA methylation profiling technologies, including MeDIP-sequencing, Illumina DNA methylation arrays, and targeted bisulfite sequencing. Rather than looking at epigenetic similarities, the project focused on epigenetic differences that may explain why many identical twins do not develop the same diseases. Initial analyses focused on obesity, diabetes, allergies, heart disease, osteoporosis and longevity, and the methodology was extended to explore over 30 common human traits and diseases. The strongest signals were obtained for epigenetic signatures of age and specific environmental exposures, such as smoking. Epigenetic signals both within and across tissues act as biomarkers of ageing and can be used to predict age, highlighting the potential of epigenetic research in healthy ageing and age-related disease. The findings also emphasize the value of using epigenetic signals as surrogates of environmental exposures, especially in existing large-scale epidemiological cohorts where such data may be limited. Epigenetic profiles of disease-discordant twins showed moderate epigenetic differences, predominantly linked to metabolic traits and cancer, identifying potential future therapeutic and preventative targets. Cell and tissue specific epigenomic profiling helped establish the molecular specifity of the findings at the organismal level, and their relevance to disease pathways. Longitudinal analyses were crucial in helping to assess whether epigenetic changes likely contribute to human phenotypes or whether they arise as a consequence of disease. The EpiTwin project has generated a unique large-scale epigenetic epidemiologic resource in 5,000 twins that has enabled the research team and multiple collaborative efforts to help tackle the complex problem of unravelling the molecular basis of ageing and human complex disease and translating it into biomarker development.