Methylomic profiling in schizophrenia: towards an integrated genetic-epigenetic approach

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Schizophrenia is a severe psychiatric disorder, characterized by psychotic symptoms, delusions and hallucinations, disorganisation, dysfunctional affective responses, and altered cognitive functioning. The social and economic consequences of schizophrenia are severe, eclipsing those of many other illnesses. With a lifetime prevalence rate of ~1%, schizophrenia contributes significantly to the global burden of disease, ranking among the top ten causes of disability in developed countries worldwide. Current approaches to understanding the causes of schizophrenia have focused primarily on uncovering a genetic contribution to the disorder, although identifying risk variants has not been straightforward. Furthermore, there is considerable heterogeneity across studies and the mechanism behind the action of genetic risk variants remains largely unknown. Despite considerable research effort, therefore, we are remain no closer to understanding the precise aetiology of SZ and a long way from realising the post-genomic promises of novel diagnostic and therapeutic strategies. Sequencing the genome was, however, only the first step in our quest to understand how genes are expressed and regulated. Sitting above the DNA sequence is a second layer of information (the 'epigenome') that mediates the regulation of when and where genes are functionally transcribed. Unlike the DNA sequence, which is stable and strongly conserved, epigenetic processes can be highly dynamic: not only are they developmentally-regulated, but they can also be modified by exposure to a range of external environmental factors and stochastic events in the cell. This study aims, for the first time, to systematically examine the role of epigenetic processes in schizophrenia, focusing on DNA methylation, a chemical modification to DNA that can directly influence gene transcription and function. We will use cutting-edge methods to examine genome-wide patterns of DNA methylation in several unique collections of samples. First, we will use a large collaborative collection of schizophrenia patients and controls. These samples have already been extensively studied at the genetic level, enabling us to undertake an integrated genetic-epigenetic approach to schizophrenia. Second, we will examine epigenetic differences within genetically-identical monozygotic twin-pairs, where one twin has schizophrenia and the other does not. Third, we will examine differences in brain tissue taken post-mortem from patients with schizophrenia. Finally, we will assess epigenetic changes across specific regions of the genome in individuals at high-risk for developing schizophrenia, tracking changes in DNA methylation with disease onset. Our proposed integrated genetic-epigenetic approach brings together a world-class group of epigeneticists, geneticists, clinicians and bioinformaticians with the ultimate goal of identifying peripheral epigenetic biomarkers for schizophrenia and transforming diagnostic, therapeutic, and future aetiological approaches to the disease.