Dr Aiden Corvin

The goal of the Psychosis Research Group is to identify and investigate the genetic architecture of schizophrenia (SZ; OMIM 181500) and related disorders. SZ is a complex brain disorder characterized by psychotic symptoms (e.g. delusions and hallucinations), negative symptoms (affecting mood and motivation) and cognitive deficits. This work is important because ~1% of the adult population are affected, representing about 24 million people worldwide. Current therapies are only partially effective. Because SZ is substantial heritability (h2~0.8) and of uncertain aetiology, identifying risk genes will be key to understanding pathophysiological mechanism(s), for molecular subtyping and in developing novel pharmacotherapies (3). Since 2002 our group (and others) have identified a number of schizophrenia susceptibility genes, including Neuregulin-1, Dysbindin, Damino acid oxidase (DAO) and Damino acid oxidase activator (DAOA) (7, 25-28). More recently we have found evidence of interaction between genes in disease risk (6,7, 22). In particular, that genes encoding components of a protein complex (called BLOC-1) which includes the dysbindin protein, are also involved in susceptibility (6). This suggests that genes involved in pre-synaptic vesicular trafficking may contribute to SZ risk (6). We are now targetting other components of the pre-synaptic vesicular trafficking machinery. With Dr Kevin Mitchell (TCD) we are also using animal models to identify gene families vital for the development of early neural networks and investigating these genes in human studies.

From 2007 our focus has shifted to comprehensive genomic studies allied to investigating the functional impact of genes. With technological developments it is possible to assay most common genetic variation in the genome, for example, to perform a genome-wide association study (GWAS) (3). This has brought about a paradigm shift from studying single genes to entire genomes as a powerful method of understanding complex genetic disorders. With European colleagues we are collaborating with MIT in a large GWAS of schizophrenia the results of which will be available later this year. With colleagues at Cold Spring Harbor Laboratory we are performing a complementary study of genomic copy number variation. We are also developing bioinformatics methods of mining GWAS data for the involvement of molecular pathways and systems in complex genetic disorders.

Using a multidisciplinary research approach we are investigating the phenotypic effects of susceptibility genes. To date we have established that certain risk variants contribute to particular clinical presentations, cognitive deficits and electrophysiological abnormalities in SZ (1,4,9,10). For example, we have identified that risk variation at the Dysbindin gene is associated with a specific symptom profile, more impaired spatial working memory, and deficits in early visual processing (1). The aim of this approach is to identify biomarkers for specific molecular pathways contributing to illness, to elucidate the neural mechanisms involved and to develop novel therapeutics strategies.

The group is funded by Science Foundation Ireland, the Health Research Board and the Wellcome Trust. We also co-ordinate the Resource for Psychoses Genomics Ireland, an all-Ireland initiative funded by the Wellcome Trust. Since 2003 we have had two completed PhD studentships and have four active PhD students.

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