Mapping the genetic architecture of global gene and exon expression in the human brain to understand common diseases

Diseases affecting the brain are common and often devastating. Unfortunately, we know relatively little about why certain people suffer from psychiatric conditions like schizophrenia, or neurological conditions like Alzheimer?s and Parkinson?s disease. However, in the past 3 years scientists have been able to show that some individuals inherit risk factors in their DNA, which make them more likely to develop these conditions. Although this has been an amazing step forward, because most of the inherited risk factors are not within the part of the DNA that codes for proteins we still do not understand how these risk factors change the way cells in the brain behave to cause disease. Without this type of information we cannot begin to develop new and more effective treatments.
The aim of our work is to fill this gap in knowledge by investigating how inherited risk factors influence gene expression in the human brain so that we can better understand the causes of neurological and psychiatric disease. We hope to identify genetic variants in the DNA which not only increase the risk of having a disease of the brain, but also affect gene expression in brain regions already known to be important in disease. In this way we can start to pinpoint the systems or pathways in brain cells, which are causing the problem and hopefully provide the basic information that will lead to new treatments.
In this study we will use human brain tissue that has been donated for research by the deceased?s family to study the effect of inherited risk factors on the quantity and type of gene expression in different areas of the brain. We will use microarray technology to obtain detailed genetic and gene expression information about human brain tissue. The huge amount of information generated will be carefully analysed. The information this study will produce is likely to be of use to many researchers investigating a wide range of different diseases of the brain. Therefore, we will make sure that the results are made publicly available as soon as possible, while at the same time ensuring that information that could be used to identify individuals is protected.
Thus, we hope to be able to improve the understanding of the molecules and pathways that cause diseases of the brain and provide the basis for new treatments for diseases like Parkinson?s or schizophrenia.

The aim of this project is to translate newly discovered genetic risk traits for complex neurological and psychiatric conditions into an understanding of pathogenesis. Until recently there seemed little hope of developing a genetic understanding of common diseases of the central nervous system (CNS). However, whole genome association studies of human disease are revolutionising our understanding of the aetiology of complex diseases, from psychiatric conditions such as drug addiction and schizophrenia on the one hand, to neurological conditions like Parkinson?s and Alzheimer?s disease on the other. These studies have demonstrated what has long been suspected, that common ?normal? variability contributes to the risk of common neurological and psychiatric disease. While some of the risk loci identified have been assigned to coding changes in genes, the majority have not, and many have not even mapped to recognisable genes.

Thus, knowing genetic risk variants for common diseases has not provided an automatic understanding of pathogenesis or obvious therapies. In order to address this problem we will study the genetic variability of gene expression within the human brain. The basis of our approach is the hypothesis that genetic differences in transcriptional regulation, which are present and measurable in control populations, are important drivers of pathology in the human CNS. If common genetic differences in transcriptional regulation can drive pathology in the human CNS, then we would expect to find strong associations between the risk SNPs identified in GWAs for neurological and psychiatric diseases and specific mRNA expression phenotypes of functional significance in control human brain.

We intend to use post-mortem control human brain tissue to collect samples from well-defined brain regions known to be particularly affected in the most common neurological and psychiatric diseases. Since risk-associated SNPs will be present in the control as well as the case population, using control brain tissue we can study downstream affects on gene expression without the complications of neuronal death, glial response and symptomatic treatments. Using microarray technology, we will produce high quality, genome-wide paired SNP and exon-specific expression data. Data analysis will be focused on identifying downstream gene expression changes associated with individual SNPs known to increase the risk of developing a neurological or psychiatric disease.

Thus, we will bridge the gap between genetic risk and pathophysiology. In this way, we will be able to point towards new therapeutic strategies for the early and effective treatment of human diseases of the CNS.