SUSCEPTIBILITY GENES FOR SCHIZOPHRENIA AND BIPOLAR DISORDER: TRANSLATING FUNCTIONAL GENOMICS TO CLINICAL PSYCHIATRY.

Schizophrenia (SCZ) and bipolar (BP) disorder are severe mental disorders, which are both ranked among the leading causes of the total burden of diseases worldwide. Despite decades of research devoted to psychotic illnesses, the understanding of underlyin g biological mechanisms is inadequate and fragmentary, and treatment often fails. It is clear that SCZ and BP are among the most heritable common diseases, with heritability estimates of 70-80%. Although research of suceptibility genes to these disorders has been challenging, several genes have been identified and are in the process of being replicated. But often classical studies fail to identify susceptibility genes and there is a need for new research strategies to unravel the genetic mechanisms of SCZ and BP. Recently, the concept of Convergent Functional Genomics (CFG) has been introduced: it uses microarray-based gene expression studies to generate lists of high probabilty candidate genes. These genes should be investigated for their effect in case control association studies. We have further developed the strategy of CFG, supported by three major pillars: 1) Expertise in global gene expression studies has led to the characterization of several strong candidate genes for major psychiatric disorders and drug response, 2) Extensive literature and database searches has provided further evidence that several of these genes might either lie in regions of linkage to psychiatric disorders or be interactors of genes that have been associated to psychiatric disorders, and 3) national and international collaborations have granted us the access to large populations of well characterized cases and control samples for associations studies in schizophrenia and bipolar disorder. We now propose to extend the gene e xpression profiling of brain regions and perform association studies to investigate whether the novel candidate genes could be involved in the etiology of SCZ and BP or the response to drug treatment.