Gene regulatory variation in the developing human brain and its role in neuropsychiatric disorders

Large genetic studies, involving many thousands of individuals, have identified several regions of the genome where DNA variation increases risk for major psychiatric disorders such as schizophrenia. However, the biological mechanisms by which these genetic variants confer risk to these disorders are currently unknown. It is believed that many of these risk variants operate by changing the amount, or 'expression', of nearby genes in the brain, and, further, that these effects start very early in brain development. To test this hypothesis, we will examine DNA variants across the entire genome and relate these to highly sophisticated measures of gene expression in the developing human brain. These studies will greatly advance our understanding of major psychiatric disorders, which will serve as a basis for improved treatments for these conditions.

Large-scale genetic studies have successfully identified genetic loci conferring susceptibility to major neuropsychiatric disorders such as schizophrenia. As the most strongly associated variants are typically in non-coding regions of the genome, it is likely that risk is commonly mediated through effects on gene expression. However, the genes that are affected, the way in which they are functionally altered (e.g. up- or down- regulation) and where and when the effects are exerted are currently unclear. Given that several neuropsychiatric disorders are thought to have a neurodevelopmental component, we will explore effects of identified risk variants for these disorders on the expression of proximally located genes in the developing human brain. One hundred foetal brain samples will be genome-wide genotyped for >1 million single nucleotide polymorphisms and the corresponding RNA deep sequenced to provide whole transcriptome measures of gene expression. We will use these data to identify those genes that are differentially expressed in the developing brain in association with neuropsychiatric risk variants and to determine the way in which they are functionally altered. We will also perform a genome-wide assessment of genes that are differentially regulated in the developing human brain as a result of common genetic variation and seek to identify downstream changes in gene expression associated with altered regulation of neuropsychiatric susceptibility genes. These studies will greatly improve our understanding of the aetiology and underlying biology of neuropsychiatric conditions as well as of gene regulation in the developing human brain.

Although neuropsychiatric disorders are common and associated with considerable individual and societal burden, we know incredibly little about the underlying neurobiology of these conditions. Elucidating the molecular mechanisms by which identified genetic risk variants operate will be an essential first step in advancing our biological understanding of these disorders, with the ultimate goal of developing improved treatments and possibly even prevention strategies.

In the short term, the primary beneficiaries of our research will be other researchers in academia and industry. Our analyses of the data, with the primary aim of identifying genetic risk mechanisms for neuropsychiatric disorders operating during foetal brain development, will particularly benefit the research of others seeking to understand the biological basis of these disorders. For example, it will foster more valid animal models for these conditions, with which improved therapies can be developed and tested. However, given its genome-wide nature, the raw and processed data will also be useful to scientists more generally; for example, by indicating novel RNA transcripts expressed during human brain development or in allowing researchers to test effects of genetic variants implicated in other brain phenotypes on gene expression in the developing brain.

We will ensure maximum impact of this research through open access publishing in leading science journals, review articles, conference presentations and extensive data sharing.