Recent twin studies suggest that childhood disruptive disorders have a substantial genetic component. One limitation of these findings is that they provide only an abstract and general characterization of these genetic influences. Molecular genetic studies are being conducted in an effort to find genetic risk factors that represent specific casual mechanisms underlying childhood disorders. Recent studies have reported association and linkage between a number of candidate genes in the dopaminergic system and childhood ADHD. Although these studies represent a useful beginning to finding genes that contribute to the risk for childhood disruptive disorders, at present we know very little regarding the complex relations between such genes and these disorders. The candidate proposes training and development in the allied areas of statistical and molecular genetics and developmental neuroscience that will provide a foundation for examining these complex relations in his research. In the proposed study, I will build on the extant findings in this burgeoning research domain by examining four specific aims regarding the association and linkage between children s disruptive disorders and DNA markers and candidate genes that code for various aspects of neurotransmitter function. First, I will test for association and linkage between a number of candidate genes and children s disruptive disorders. Second, I will examine heterogeneity in association and linkage of candidate genes with disruptive disorders due to the characteristics of the disorders, participants, and their environments. Third, I will use lab measures of executive functions to help find association and linkage with the disruptive disorder phenotypes, and as endophenotypic mechanisms to test whether they mediate the relations between candidate genes and childhood disruptive disorders. Finally, I will collect data from sibling pairs to prepare for a genome scan that will examine linkage between DNA markers and disruptive disorders. The development and training component will include mentorship by experts in the areas of statistical and molecular genetics and developmental neuroscience and psychopathology, as well as related coursework. This training will be applied in a molecular genetic study of disruptive disorders, sampling 400 clinic-referred children and their families, that will address the specific aims above. The proposed training program will help the candidate become an independent researcher in the burgeoning area of the molecular genetics of childhood psychopathology. The proposed study will increase substantially our understanding of specific genetic influences on the childhood disruptive disorders.
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