Regulatory genomic profiling in schizophrenia

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.

We propose the first comprehensive analysis of regulatory genomic variation associated with schizophrenia. Given evidence for a neurodevelopmental component to the aetiology of 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.

We will first profile key markers of genomic regulation (DNA methylation (5mC), DNA hydroxymethylation (5hmC), and lysine H3K27 acetylation (H3K27ac)) in purified neuronal nuclei isolated from post-mortem prefrontal cortex tissue from >400 schizophrenia cases and matched controls.

We will next extend these analyses to human fetal cortex samples spanning ~7 to 20 weeks post-conception, enabling us to annotate functional genomic domains in the developing cortex and test the hypothesis that there is an enrichment of neurodevelopmentally-dynamic loci in regions of schizophrenia-associated regulatory genomic variation.

Alternative splicing and RNA isoforms dramatically increase the protein-coding potential of the human genome during development. Our third aim is to employ novel long-read sequencing approaches to undertake the first comprehensive analysis of RNA splicing and isoform diversity in both the developing and adult human cortex, exploring the role of alternative splicing in schizophrenia.

Finally, we will examine how schizophrenia-associated genetic variation influences regulatory genomic processes in the developing and adult cortex, building on our recent work showing that schizophrenia GWAS loci are enriched for 5mC quantitative trait loci in the developing brain.

Building on findings from our previous MRC-funded research, our integrated-genomics approach will enable us to explore the dynamic regulation of gene function during human brain development and its relevance to the aetiology of schizophrenia.

In addition to other scientists (especially other research groups investigating neurodevelopment and the aetiology of schizophrenia) the results of this project have the potential to impact on a number of other beneficiaries. These include patients suffering from schizophrenia, the pharmaceutical industry, health service providers, and academic groups investigating the causes of other complex disease phenotypes.

The social and economic consequences of schizophrenia are severe, eclipsing those of many other mental and somatic illnesses. With a lifetime prevalence rate of ~1%, the disorder contributes significantly to the global burden of disease, ranking among the top ten causes of disability in developed countries worldwide. Importantly, there is no cure for schizophrenia, and available treatments are often inefficient and characterised by severe side-effects. Given the dynamic and potentially-reversible nature of the epigenome, the outputs from this research could potentially nominate new targets for drug development for the treatment of schizophrenia. A number of pharmaceutical companies are actively developing so-called "epigenetic drugs" and could rapidly take advantage of these outputs. Our data may also highlight novel neurobiological pathways involved in schizophrenia, again stimulating the development of novel therapeutic interventions. Developing new treatments for schizophrenia will have subsequent benefits to the family and friends of affected individuals, and potentially boost the economy by enabling affected individuals to return to work. Of note, we work extensively with industrial partners and were recently funded by Eli Lilly's Lilly Research Award Program to undertake systems level genomic connectivity mapping in neural cell lines exposed to a panel of test compounds relevant to schizophrenia.

We propose to employ a range of cutting-edge technologies to undertake this work and develop novel strategies for performing integrated systems-level genomics analyses. This has the potential to not only benefit those scientists directly employed to work on the project, but may stimulate research into developmental genomics more broadly across the life sciences sector in the UK and beyond.

We are committed to communicating the impact of our research not only through standard scientific activities (high impact journals, conference attendance, and presentations at scientific seminars) but also via more accessible fora, such as our lab website (http://www.epigenomicslab.com/), Twitter (https://twitter.com/PsyEpigenetics) and the media (see http://www.epigenomicslab.com/media/ for media case-studies). Information arising from the proposed research will be communicated to the public following consultation with the host institutions and the MRC Press Office. Advice on dissemination of this research will also be sought from the host department, which has a strong track record in the public dissemination of scientific findings.

Finally, we hope that our novel integrated genetic-epigenetic approach to schizophrenia may stimulate similar research strategies to be adopted by academics working in the context of other complex disease phenotypes.