Molecular Genetics of Schizophrenia

Schizophrenia is a severe psychiatric disorder, which affects approximately 1% of the population. It is characterised by so-called psychotic symptoms, in particular delusions (false beliefs) and hallucinations (false perceptions), the latter being often in the form of hearing voices. Sufferers also tend to show altered emotional reactivity, impairments of thinking and reasoning and bizarre behaviour. Signs can be present from early childhood, but usually the disorder has its clinically detectable onset in the late teens and early 20?s. This age of onset, combined with the facts that many patients respond poorly or even not at all to any form of treatment, and for those that do respond, relapse is usually frequent, mean that the illness typically impacts on the vast majority of an individual?s adult life. This makes schizophrenia a major burden on the patient, their family and wider society. It has been clear for a century that schizophrenia runs in families, and this is now known to be largely due to genes rather than the family environment. Schizophrenia is clearly a brain disease but in spite of much research, it has not been possible to identify specific brain abnormalities that cause the disorder. Such knowledge is likely to be required for the development of truly effective treatments. It is our belief that the best hope of identifying the abnormalities that underlie schizophrenia is to identify the nature of the genetic susceptibility. This has proven difficult because schizophrenia, like other common diseases, does not occur as a result of a single genetic mutation, but reflects the operation of a large number of ?risk genes? each of which is responsible for only a small increase in risk of the disorder. It is really the combination of genes inherited at birth that determine someone?s risk. Modern genetic methods are, for the first time, allowing the great majority of variation in a person?s DNA to be assessed in a single experiment. If this technology is applied to a sufficiently large number of people, it is possible to identify risk genes that cause even fairly small increases in risk for a disease. This approach has been successfully applied to other common diseases such as asthma, diabetes, heart disease etc. We are proposing to use similar methods in large samples of patients that we and our collaborators have assembled over many years, precisely with a view to undertaking these studies.

Schizophrenia (SZ) has a heritability of more than 80%. Population risk seems mainly attributable to alleles of small effect, although loci of larger effect exist in some families. Identification of specific risk genes should advance our currently vague understanding of pathophysiology. Several strong candidate genes for SZ have been identified, but the evidence falls short of the stronger findings that have emerged from Genome-Wide Association (GWA) studies of common medical disorders. Moreover, the great majority of genetic risk for SZ is still unaccounted for.
The successful applications of GWA to common disorders have been based on large samples and, crucially, from follow-up analyses in even larger samples. Work on psychiatric disorders is less well developed, largely due to the difficulty in assembling the samples of sufficient size. Our own early GWA findings employing a relatively small discovery sample of 479 cases but with nearly 3000 controls and follow-up in a sample of 6870 cases and 9914 controls provided compelling evidence that one or more variant in the vicinity of ZNF804A, KCNA4, and RPGIPL1 contributes to SZ susceptibility. No other SZ candidate genes are currently supported by consistent data from individual SNPs in samples of this size at the same levels of statistical significance.

We will undertake fine mapping to localise and identify the likely susceptibility variants in these genes, and their effects on gene function. We will also conduct similar analyses of new data emerging from our separately funded programme of sample collection, and from the extensive GWA data that will become available to us through the many collaborative studies and analyses that are underway in which we are centrally involved. In doing so, we aim to provide indisputable evidence for the individual genes, and novel insights into schizophrenia pathogenesis. We will also seek risk loci by analysis of functionally related groups of genes using novel statistical approaches that we have developed.
There is strong evidence for significant genetic as well as symptomatic overlap between schizophrenia and the other major functional psychoses, schizoaffective disorder (SA), bipolar disorder (BD) and related disorders, and our associations to ZNF804A and KCNA4 appear to be examples of overlapping risk. Thus the second major aim of our work will be to determine whether risk for SZ is also associated with risk for additional psychiatric phenotypes and whether risk alleles are associated across diagnoses with particular symptoms or symptom dimensions.