Two domains have been robustly implicated in the etiology and pathophysiology of attention deficit hyperactivity disorder (ADHD). First, family, twin, and adoption studies have demonstrated that genetic factors play a substantial role in its etiology. Segregation analysis and molecular genetic studies have provided further support for a significant genetic component in ADHD. Second, although the details of ADHD?s pathophysiology have yet to be worked out, numerous studies have demonstrated biological abnormalities among ADHD patients. These abnormalities have been demonstrated both indirectly, as in neuropsychological assessment, and directly as in neuroimaging studies. The available data strongly suggest that a substantial component of ADHD?s etiology is mediated by gene expression in the central nervous system. However, a detailed understanding of the genetics of ADHD must overcome several hurdles. Paramount among these are the potential for genetic heterogeneity among ADHD and the likelihood that subforms of the disorder have a complex mode of inheritance. The main goal of the proposed research is to detect one or more genes responsible for the genetic transmission of ADHD. The main strategy of this proposal is to perform quantitative trait locus (QTL) sibling pair analysis using 400 microsatellite markers (simple sequence repeats, SSRs) which span the genome at 10 centimorgan (cm) intervals. This is expected to identify regions in the human genome containing QTLs for ADHD and to lay the foundations for fine mapping to identify one or more genes that mediate the susceptibility to ADHD. The three aims of the proposal are to ascertain a large sample of sib-pairs concordant and discordant for ADHD, to apply QTL linkage mapping approach to ADHD, and to create a resource for the fine mapping of ADHD genes. The project will make use of a collaborative framework in order to ascertain a total of 800 sibling pairs in eight countries. The collection of such a large international sample will provide the statistical power needed to detect the expected size of gene effects, and will create a resource of 800 nuclear families suitable for future family-based association studies and for subsequent fine mapping and genomewide association mapping of ADHD genes.
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