We intend to examine oligodendrocyte/myelin related (OMR) genes in schizophrenia in order to identify those specific OMR genes that initiate the pathophysiological processes in schizophrenia. By identifying new genes, we will also provide etiologically relevant foci for other CCNMD components whose aims are to elucidate the pathophysiological cascades through cell biology and animal models. We will also enable externally validated exploration of the diagnostic boundaries of psychosis and of endophenotypes, and the construction of etiologically relevant animal models in which to explore pathophysiology, develop novel endophenotypes and markers of disease, and model novel therapeutic interventions. Aim1. Identify causal pathways: Genes that regulate oligodendrocyte development and maturation will be tested by genetic association based on whole genome data plus additional focused genotyping, and by replication in large samples. Aim 2. Determine how OMR genes relate to white matter imaging abnormalities in schizophrenia and to clinically important neuropsychological measures. Genes associated from aim 1 will be examined in subjects who have had diffusion tensor imaging and neuropsychological profiling. Aim 3. Determine how OMR genes relate to the clinical phenotype. We postulate that OMR genes confer risk beyond diagnostic boundaries, and may influence particular domains of psychopathology and/or clinical outcome. We will test this by examining genes associated from aim 1 in large samples of individuals with schizoaffective disorder, bipolar disorder and psychotic unipolar disorder. We will also examine relationships with the clinical variables we have collected with the minimal imposition of nosological models. Aim 4. Identifying Animal Models. Mouse strains carrying spectra of nonsense and missense mutations in the genes identified as mediators of schizophrenia risk will prove of value in identifying the functions, normal and pathogenic of the susceptibility genes, the disease mechanisms, and in the development of treatments. We will identify mouse mutants for key OMR genes by screening DMA from the MRC UK Harwell END series. The work proposed relates to improving mental health on several levels. New understandings of fundamental disease mechanisms will ultimately lead to new therapeutic opportunities. We also expect to contribute to the development of improved diagnostics and classification based upon etiology and pathophysiology. Success here will have wide ranging consequences for all clinical and research that use psychiatric classification, including diagnostics and treatment.