This is an application for a Mentored Clinical Scientist Development Award with a focus on developing expertise in the design, analysis and interpretation of psychiatric genetic studies. The candidate proposes a concentrated and comprehensive period of training and supervised research in genetic methods. Anxious temperament in the form of """"""""behavioral inhibition to the unfamiliar"""""""" (BI) is a heritable, biologically-based and evolutionarily-conserved phenotype, which has been linked to familial risk for anxiety disorders. As such, it provides a unique opportunity to study the genetic basis of anxiety disorders. The identification of genes influencing anxious temperament would signal a major advance in our understanding of the molecular basis of temperament and psychopathology and might contribute to the development of targeted prevention and treatment strategies of anxiety disorders. Research Plan: The proposed research will begin with a phenotypic analysis of BI to identify features, which most closely reflect genetic influences. Based on statistical modeling of phenotypic data from an existing database of children with BI and their families, factors, which predict ascertainment of families with multiple affected offspring, will be identified. An optimized phenotype definition will then be constructed to maximize the sibling recurrence risk ratio associated with BI. These analyses will be used to inform subsequent association and linkage studies. A genetic resource of DNA collected from participating families will provide the basis for a program of molecular genetic research on BI, including family-based association analysis of candidate loci derived from genetic studies of animal models. Finally, the collection of DNA from small nuclear families of children with BI will serve as the foundation of an anticipated whole genome scan to be completed after the period of this award. Career Development Plan: Career development activities will focus on providing the candidate with training in genetic study design, statistical genetics and molecular genetic approaches to complex traits. These activities will include courses in statistical genetics at the Harvard School of Public Health, courses in the use of genetic analysis software at Case Western Reserve University and Rockefeller University, and training in the use of mouse models and quantitative trait locus mapping at the Jackson Laboratories. Tutorials and supervised study with the consultants will focus on phenotype definition and genetic epidemiology as well as statistical and molecular methods of linkage and association analysis. This integrated program of training and research in genetic methods will prepare the candidate to be an independent investigator in the rapidly evolving field of psychiatric genetics.
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