Molecular Genetic Studies of Schizophrenia

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.

We aim to build on recent advances in schizophrenia genomics to implicate genes, individual mutations and specific biological processes, and identify novel patient strata. Our first goal is to implicate rare exonic mutations and specific genes by whole exome sequencing of patient-proband trios, cases and controls. The funding requested will bring our total UK sample to 16000 cases and 16000 controls plus 2109 trios. These data will be used to identify de novo mutations, conduct case control analyses and undertake combined analyses of mutations of all classes [de novo and standing, single nucleotide variants (SNVs) and CNVs]. Replication studies and formal mega-analyses will be conducted though our large network of collaborators. This will enable us to identify specific pathogenic genes, and both pathogenic and protective mutations. Second, using a variety of gene-set enrichment approaches applied to both GWAS and sequencing data, we will identify and refine specific sets of functionally related genes that are enriched for genetic risk alleles. This will bring to bear novel genomic annotations and other -omics data (transcriptomics, methylomics and proteomics). Finally, we will seek to identify phenotypically defined strata that can be distinguished genetically. This work will be based on an increasingly refined genetic signal at the individual mutation, genic, gene-set and genomic levels, use dimensional as well as categorical approaches and include unbiased approaches based upon canonical correlation analysis as well as hypothesis driven approaches. Our work will deliver fundamental insights into the biology of schizophrenia, provide the resources and reagents (in the form of actionable causal and protective mutations, implicated pathogenic pathways and valid patient strata) that will drive mechanistic and translational research, deliver novel therapeutic targets, and inform clinical practice.

The main aims of our programme are to use genomics to a) implicate specific biological processes, genes, and mutations to serve as a basis for future mechanistic studies, and b) to conduct genomic analyses across schizophrenia and related neurodevelopmental and psychotic disorders in order to identify novel strata for clinical and interventional studies. The personal and economic burden of these disorders is the largest of all categories of disorder and the development of more effective therapies is a pressing requirement for global health and wellbeing. There will thus be many beneficiaries of our work including academic and industry researchers, sufferers, their families, and the health service and the wider population upon which much of the economic burden falls.
This work will be of direct benefit and interest to a broad group of industry researchers as well as to academic researchers outside the immediate professional circle of those carrying out psychiatric genetics research. In particular the identification of specific risk genes and mutations (short term benefits) will provide benefit to a) clinical neuroscientists seeking to understand the impact of genetic risk on brain structure and function by stratifying subjects on the basis of genotype and b) basic neuroscientists seeking to develop novel cellular and animal models of psychiatric disorders with high construct validity based upon high penetrance mutations. These are required to understand disease mechanisms and identify novel treatment targets. The development of new more effective treatments (medium to longer term benefits) will have positive impacts on health, quality of life and the economy; both directly through profits to pharma and indirectly through improved care, reduced care burden and increased economic productivity. We also intend, through other funding, to establish and bank cell lines from fibroblasts or keratinocytes and to derive iPSC from selected cases carrying high penetrance mutations. These will be made available through the CoSyn project (short term benefits) to a network of other academic and industrial collaborators (Lundeck, Hoffmann-La-Roche and Pfizer) as well as to bona fide researchers and industry investigators.

Our genetic findings have already spearheaded contemporary debate about psychiatric classification and diagnosis. Our future findings on the genetic overlaps and distinctions between current diagnostic groups and the identification of novel strata will continue to inform this debate as psychiatry moves inexorably from the current descriptive system to one that is more in tune with underlying pathogenesis (on-going benefits). This will be of relevance to the development of novel diagnostic systems (DSM and ICD) and to clinical researchers and pharma, informing the design of clinical trials and the provision of precision medicine. Our findings will also be of relevance to population and clinical scientists by allowing hypothesis-driven studies of causal processes in the general population as well as in clinical samples and longitudinal and quasi-experimental designs. This will inform future intervention policies (longer term benefits). Finally our work will be relevant (short and longer term benefit) to the health service by contributing key data that can be implemented for early diagnosis and identification of those at risk of subsequent psychiatric and neurodevelopmental disorders. The resulting reductions in morbidity and mortality will benefit health and the economy.

The staff working on the project will receive training in genomics, statistics, bioinformatics, neuroscience, psychology and psychiatry. Their skills are applicable not only in academia but also more widely including in industry, the NHS, education and policy making.