The interplay between environmental factors and DNA methylation in psychotic disorders : Environmental orchestration of the epigenome

Introduction: Environmental exposures during early- life increase the risk of developing a psychotic disorder, but it remains unclear how early life events can have such persistent later life consequences. DNA methylation is the addition of a methyl group to a DNA base and is part of a group of epigenetic mechanisms that together can influence gene expression. Since DNA methylation can reflect environmental influences over time, it is a potential mediator of the early life environmental influence on psychotic disorders. Therefore, this thesis examined the interplay between environmental exposures relevant for psychotic disorders and DNA methylation. Results: Early-life stress is hypothesized to alter the stress response system and consequently increase the risk for a psychotic disorder. Thus, we first examined if stress reactivity could be a marker for disease vulnerability in bipolar patients. Indeed compared to healthy controls bipolar patients exhibited altered stress reactivity, specifically increased release of the autonomic nervous system marker alpha amylase and blunted levels of the stress hormone cortisol. Upon further examination the blunted cortisol stress reactivity in bipolar patients was primarily related to antipsychotic use, suggesting medication is a more important modifier of cortisol stress reactivity than other factors such as disease status. In a subsequent study we show medication use by bipolar patients also influenced blood DNA methylation levels and should be considered a confounder in methylation studies. Together these two studies demonstrate the importance of thorough phenotyping in observational DNA methylation and stress studies. Next, we describe a DNA methylation locus on the Kit ligand (KITLG) gene that partly mediated the relationship between childhood trauma and cortisol stress reactivity in healthy controls. This extends preclinical findings that DNA methylation regulates stress reactivity to humans. Finally, we report on a hypermethylated promoter region that is not only associated with famine exposure in schizophrenia patients, but also with schizophrenia in general. This highlights that DNA methylation is a valuable biological mechanism to examine for environmental exposures and provides tentative evidence of DNA methylation marks as an indicator for disease risk. Conclusion: Overall, the results described in this thesis are consistent with the concept that DNA methylation is an underlying mechanism conferring environmental impact on disease risk for psychotic disorders. More knowledge of how DNA methylation is related to disease can provide essential new leads for treatment and prevention and, ultimately yield new drug targets