Although DSM-IV and its predecessors follow a categorical, syndromal nosology, It has long been recognized that there is considerable phenotypic overlap across diagnoses. Consequently, recent attention has been increasingly focused on dinnensional, symptom-based approaches toward untangling the pathophysiology of serious mental illness (for example, those with psychotic features). Similarly, the distinction between illness and health is often treated as dichotomous;yet recent evidence suggests that the phenotypic variations associated with psychosis may be informatively examined using dimensional measures applied to non-clinical samples. Unfortunately, there is a paucity of data on the dimensionality of the behavioral phenotypes associated with psychotic and other serious mental illnesses, and even less data seeking to elucidate the biological mechanisms responsible for this variation. Nevertheless, the psychiatric genetics literature to date provides strong suggestions that pathogenic variations do not respect traditional diagnostic boundaries, and may be more strongly associated with specific symptom domains. The proposed research plan aims to elucidate the genetic underpinnings ofthe dimension of psychosis. Specifically, the K99 portion of this project identified several genetic variants that demonstrated association to distinct phenotypes that crossed traditional DSM-IV boundaries in a sample of evaluated test candidate genes for association with dimensions of psychosis in a large, diagnostically heterogeneous sample. The ROO aims to investigate the relation between these genetic variants and dimensions of sub-clinical psychosis in 1,000 subjects derived from a non-clinical sample.
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