Using Genetics to Dissect Schizhoprenia, Bipolar Disorder, and Depression

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DESCRIPTION (provided by applicant): Schizophrenia (SCZ), bipolar disorder (BPD), and major depression (MDD) are responsible for an enormous burden of disability, personal suffering, and economic cost. Despite progress in the diagnosis and treatment of these disorders, crucial questions about their definition and etiology remain. The best-established risk factor for these disorders is genetic vulnerability, and the identification of susceptibility genes offers tremendous hope for the development of more effective treatment and prevention strategies. However, progress in this area has been limited by fundamental uncertainties in how psychiatric phenotypes are best defined. Genes appear to influence component phenotypes that cross DSM-IV diagnostic boundaries and that may have substantial impact on illness morbidity and even mortality (e.g., suicidality). This proposal is a response to RFA-MH-07-010 "Treatment Response: Linking Genes with Behavioral Phenotypes of Relevance to Patients, Families and Policymakers". It represents the first, adequately powered study to dissect genetic influences on SCZ; BPD, and MDD as well as disabling symptoms and functional impairment that may be independent of diagnostic categories. This will be accomplished by combining phenotypic and genetic data from three large multicenter NIMH-funded treatment studies-the CATIE study of SCZ (N = 770), the STEP-BD study of BPD (N = 2090), and the STAR*D study of MOD (N = 1953)-as well as a large sample of screened controls (N = 2000). The aims of the study are to 1) create a composite phenotypic database from these cohorts and derive key phenotypic variables for genetic analyses; 2) genotype 768 SNPs in 15 genes selected for having the strongest prior probability of involvement in the mood- and psychosis-related phenotypes; 3) perform analyses to determine whether phenotypic effects of these genes (a) support nosologic distinctions among psychotic and mood disorders and (b) influence clinical features (psychosis, suicidality) and functional outcomes independent of diagnosis. The proposed research will address fundamental questions about the nosology and genetic etiology of major mental illness and its functional consequences. As such, it will have implications for informing both the biological and clinical understanding of mood and psychotic disorders. Finally, the phenotypic and genetic database derived from these analyses will provide a valuable resource for future genetic studies by the scientific community.