Global gene expression of human and rat brain: an integrative genomics study of CNS functions and genetic susceptibility in schizophrenia

Schizophrenia (SCZ) is a serious psychotic disorder ranked among the 10 most disabilitating disesases worlwide (WHO) with a lifetime risk of 1% in the general population. Despite decades of research, the understanding of underlying biological mechanism re mains inadequate and fragmentary and treatment often fails. It is estimated that SCZ has a heritability of 70-80%, but research for susceptibility genes has proven challenging and so far only about 7 to 10 genes with small odds ratios have been identified and reasonably replicated. Recently the concept of Convergent Functional Genomics was introduced as a new strategy to identify candidate genes in complex disorders; it uses microarray-based gene expression studies to select genes which can be examined in downstream association studies. We have used this approach to generate maps of region-specific and "CNS signature" genes in rat brain, with a special focus on brain regions that are thought to be involved in the pathophysiology of SCZ, such as frontomedi al and temporal cortex and hippocampus. The overall objective of the project is to integrate information about novel region-specific gene expression patterns in normal brain and well-established pathophysiological findings in schizophrenic patients, to id entify new genetic risk factors involved in disease susceptibility of schizophrenia and in cognitive performance. The study will be extended with gene expression analysis of human post-mortem brain samples from selected regions. We also intend to function ally classify currently unknown CNS-expressed genes, using an integrative genomics approach. Large-scale case-control association studies will be performed on the selected sets of region-specific brain genes in schizophrenia and cognition. The final goal is to link these in house-postulated candidate genes with disease susceptibility, diagnosis-independent endophenotypes and treatment effects, tracing mechanisms from the molecular genetics to the clinical level.