We intend to examine oligodendrocyte/myelin related (OMR) genes in schizophrenia in order to identifythose specific OMR genes that initiate the pathophysiological processes in schizophrenia. By identifying newgenes, we will also provide etiologically relevant foci for other CCNMD components whose aims are toelucidate the pathophysiological cascades through cell biology and animal models. We will also enableexternally validated exploration of the diagnostic boundaries of psychosis and of endophenotypes, and theconstruction of etiologically relevant animal models in which to explore pathophysiology, develop novelendophenotypes and markers of disease, and model novel therapeutic interventions.
Aim1. Identify causalpathways: Genes that regulate oligodendrocyte development and maturation will be tested by geneticassociation based on whole genome data plus additional focused genotyping, and by replication in largesamples.
Aim 2. Determine how OMR genes relate to white matter imaging abnormalities in schizophreniaand to clinically important neuropsychological measures. Genes associated from aim 1 will be examined insubjects who have had diffusion tensor imaging and neuropsychological profiling.
Aim 3. Determine howOMR genes relate to the clinical phenotype. We postulate that OMR genes confer risk beyond diagnosticboundaries, and may influence particular domains of psychopathology and/or clinical outcome. We will testthis 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 variableswe 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 ofschizophrenia risk will prove of value in identifying the functions, normal and pathogenic of the susceptibilitygenes, the disease mechanisms, and in the development of treatments. We will identify mouse mutants forkey OMR genes by screening DMA from the MRC UK Harwell END series. The work proposed relates toimproving mental health on several levels. New understandings of fundamental disease mechanisms willultimately lead to new therapeutic opportunities. We also expect to contribute to the development ofimproved diagnostics and classification based upon etiology and pathophysiology. Success here will havewide ranging consequences for all clinical and research that use psychiatric classification, includingdiagnostics and treatment.
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