| Abstract |
Schizophrenia (SZ) is a severe psychiatric disorder. Treatments are often only partially effective, or not effective at all, and people with SZ can be profoundly disabled for most of their adult life. Developing better treatments for SZ is one of the most important challenges facing modern medicine but our ability to meet and overcome this challenge is hindered by a lack of detailed knowledge about the range of biological processes that cause the disorder. It is also obstructed by a lack of objective tests with which to make a diagnostis or classify patients into subgroups who might benefit from different treatments. We aim to use modern genetic tools to address these gaps. We know that genes are important in determining how likely people are to develop SZ, and that many genes are involved. In recent years, we have identified specific genes and mutations that contribute to risk, and in doing so, we are gaining insights into some general disease mechanisms. Most of the risk for SZ is not yet linked to specific DNA variants, but the findings we have made are pointing to abnormalities in proteins that regulate how neurones in the brain communicate with each other and are pivotal to memory and learning. The findings also show that the genes, and therefore the mechanisms, influencing SZ frequently overlap with those that influence other psychiatric and brain developmental disorders including bipolar disorder, autism, and intellectual disability. There is clear evidence that the genetic contribution to SZ includes DNA variants (risk alleles) that are fairly common but each only slightly increases risk; many of these have now been identified. It also includes alleles that are rare but confer very large increases in risk of disorder; fewer of these have been identified. Our approach in the current proposal is to apply the new DNA sequencing technology to our very large samples aiming to identify rare risk alleles of large effect. Rare alleles can be particularly informative for suggesting both disease causing and protective mechanisms. Moreover, the effects of rare mutations with big impacts on disease can be effectively modelled in cells or in animals; thus our study will provide much needed resources for the mechanistic studies that have transformed understanding of other disorders, for example cancer. Our laboratory focus is on rare mutations, but we will also integrate the findings with the results of the genetic studies of common variation we are involved in to gain a more comprehensive picture of the causes of SZ. We will use the data to identify broad biological processes that tend to be enriched for the risk alleles, and then isolate from those more specific pathogenic sub-processes that contain the genetic signals for the disorder. This sort of approach has already been successful with the moderate number of risk alleles we have previously identified. We believe that in doing so, we can make major contributions to understanding the fundamental biological mechanisms behind SZ. We will also use the findings to investigate if particular groups of patients within SZ and across SZ and related disorders can be identified in which members are enriched for risk alleles in particular biological processes. Success here will begin to allow the first biologically valid classifications in psychiatry, thus addressing one of the other major knowledge gaps and lead to improved clinical and interventional studies in psychiatry. We believe completion of these aims will deliver insights into the fundamental biology of SZ, will deliver novel targets for treatments, influence clinical diagnostics, and will provide the resources and reagents (in the form of causal and protective mutations, pathogenic pathways, and information about valid patient groupings) that will set the fundamental and clinical translational agenda in psychiatry for the next decade. |
