Recent genome-wide association studies (GWAS) of disorders such as schizophrenia have identified hundreds of genomic regions containing variants robustly associated with disease. The majority of these variants reside in large regions of strong linkage disequilibrium and do not index coding variants affecting protein structure. There remains considerable uncertainty about the causal genes involved in disease and the way in which they are functionally regulated by associated risk variants. In an attempt to localize the functional consequences of disease-associated variants, we are characterizing DNA methylation quantitative trait loci (mQTLs) in human brain and relating these to genetic findings from neuropsychiatric disorders.
Environmental and pharmacological epigenomics
Many epigenetic marks are malleable, responding to factors in both the external and internal milieu, and providing a mechanism for the interaction of the genome with environmental exposures, which is a key pathway to disease pathogenesis. We are exploring how disease-associated nutritional, chemical, physical and psychosocial factors mediate changes to the epigenome, particularly at the level of DNA methylation. We are also exploring how epigenetic processes mediate cellular responses to pharmacological agents, particular focussing on changes in human neuronal cells induced by antipsychotic agents.
Population and twin cohorts
A powerful approach in epigenetic epidemiology is the use of prospective cohort studies that allow the assessment of epigenetic changes over time and the ability to see how these patterns relate to temporal changes in exposure and disease prevalence. The longitudinal analysis of epigenetic changes in a population cohort of monozygotic (MZ) twins is a strategy that can be particularly informative for understanding epigenetic variation and its links to disease. MZ twins share their DNA sequence, parents, birth date and sex, and are likely to have experienced a very similar prenatal environment. We are currently undertaking epigenomic studies within the E-Risk twin cohort, and have just launched a twin birth cohort in the South-West of the UK.