Understanding how genetic variations interact with an environmental exposure (GxE) is a critical step in predicting long-term health. For example, genetic differences between individuals influence the likelihood to develop adult mental health disorders triggered by adversity in early-life. The development of such disorders is hypothesized to be linked to environmentally-induced epigenetic modifica-tions, such as DNA methylation, at regulatory regions of genes linked to adult stress responses. DNA variations (polymorphisms) between individuals at these key regions could determine those sensitive to developing long-term effects following early-life adversity. However, it is difficult to identify these key regulatory regions in humans as we are all uniquely individual both genetically and environmentally.
We will develop and test a strategy to discover polymorphisms regulating GxE using a translational mouse model to control for genetic variation under a regulated environment together with an integrated genetic and epigenetic genome-wide approach. As proof of principle we will perform association studies with polymorphisms and DNA methylation at homologous regions in the longitudinal ALSPAC study of early environmental outcomes.