Regulatory genomic profiling in schizophrenia

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Schizophrenia is a severe psychiatric disorder, characterised 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. Although the symptoms of schizophrenia do not typically appear until late adolescence or early adulthood, evidence from neuroimaging, neuropathology and epidemiological studies indicate that it is a neurodevelopmental disorder, influenced by risk factors with effects during prenatal development of the brain. To date, however, the neurobiological mechanisms underlying the disorder remain largely undefined, and molecular evidence linking neurodevelopmental dysfunction to schizophrenia is limited. Studies into the causes of schizophrenia have focused on describing the genetic contribution to the disorder. Recent genome-wide association studies (GWAS) of schizophrenia have been highly successful, identifying over 100 regions of the genome associated with risk. Despite this success, however, there remains uncertainty about the specific causal genes involved in schizophrenia, and how their function is regulated in development and disease. 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. These mechanisms play a critical role in determining cell-type-specific patterns of gene transcription in the human brain.This study aims, for the first time, to systematically examine the role of these regulatory genomic processes in schizophrenia. We will purify neuronal nuclei from a unique collection of post-mortem brain samples with the goal of identifying novel pathways involved in the disease. Given evidence for a neurodevelopmental component to schizophrenia, we will also annotate patterns of gene regulation across development of the human cortex, enabling us to explore the hypothesis that disease-associated loci are dynamically regulated during this critical period. Building on novel findings from our previous MRC-funded research, our integrated-genomics approach will bring together a world-class group of investigators and collaborators to explore the dynamic regulation of gene function during human brain development and its relevance to the aetiology of schizophrenia.