Schizophrenia is a severe neuropsychiatric disorder that is hypothesized to result from disturbances in early brain development. There is mounting evidence to support a role for developmentally regulated epigenetic variation in the molecular etiology of the disorder. Building on our recent publication in Genome Biology, we are currently undertaking a systematic analysis of schizophrenia-associated epigenetic variation in multiple regions of the adult brain and relating these findings to our genomic analyses of human fetal brain development. We are also funded by the MRC to undertake a large integrated genetic-epigenetic study of schizophrenia, profiling DNA methylation in samples included in recent large collaborative GWAS efforts. Finally, we are examining epigenetic variation in monozygotic twins discordant for schizophrenia and other psychotic disorders.
Autism spectrum disorder (ASD) defines a collection of complex childhood neurodevelopmental disorders affecting ~1% of the population and conferring severe lifelong disability. In a collaboration with Dan Geschwind at UCLA we are funded by the NIH to examine epigenomic differences in autism brain. We are also examining epigenetic differences in autism-discordant monozygotic twins. Finally, building on epidemiological data linking advanced paternal age to an increased prevalence of autism and related disorders, we are examining genomic changes in the offspring of older fathers using animal models and human cohorts, assessing the degree to which these mediate neurobiological phenotypes.
Depression is the leading cause of disability worldwide, and is a major contributor to the global burden of disease. Depression is associated with a reduced life expectancy and constitutes a major risk factor for suicide. We are undertaking a series of studies using post-mortem brain tissue and longitudinal studies of discordant monozygotic twins to identify the causes and consequences of epigenetic variation in the aetiology of depression. In addition to examining the molecular signatures of depression, we are looking at how environmental risk factors such as chronic stress can impact upon normal neurobiological function in the human brain.
A history of psychiatric illness is a major risk factor for suicide, a leading cause of mortality among young people in developed countries. Every year, almost one million people die from suicide globally with suicide attempts up to twenty times more frequent than completed suicide. The risk for suicidal acts is multifactorial, and consists of a range of biological, psychiatric, psychosocial and cultural risk factors. Currently, the molecular pathology of psychiatric illness leading to suicide remains poorly understood. Building on our recent publication examining DNA methylation in brain samples from depressed suicide completers, we are currently undertaking a meta-analysis of suicide-associated DNA methylation changes in post-mortem brain samples. We’re also interested in lemmings and are developing plans to build a lemming suicide cliff in a bespoke facility on the outskirts of Exeter.