Child Attention Deficit Hyperactivity Disorder (ADHD) represents a significant public health concern because it is common, costly, impairing, and chronic, placing children at substantial long-term risk. Since genetic and contextual factors are crucial to the development of ADHD, this proposal will elucidate molecular genetic mechanisms via multiple integrated strategies. Understanding of the specific molecular genetic correlates can influence definition of meaningful etiological subgroups, developmental course and pathophysiology, enabling early intervention and prevention. Using already obtained samples, haplotype discovery is proposed to establish the genomic structure in twelve theoretically relevant candidate genes involved in catecholamine synthesis and neuro-transmission. Then, with those samples and new samples to be obtained in this study, the haplotypes elucidated will be evaluated for association and linkage with ADHD, using family based TDT-type analyses. The first of these analyses will address links to symptom phenotypes, including ADHD DSM-IV subtypes and comorbid subtypes such as ADHD plus conduct disorder. We will examine categorical and continuous symptom measures. The second set of analyses will examine a battery of theoretically derived neuro-cognitive endophenotypes that either pilot data or theory suggest may relate to genetic transmission in ADHD. The neuro-cognitive model emphasizes a two-process conceptualization designed to capture both executive function components (e.g., behavioral inhibition) and delay-reward gradient and state regulation factors. We expect to be able to detect small effect sizes of the candidate genes using our approaches. The structure of the model and the analyses are designed to break new ground in identifying etiological heterogeneity in ADHD as well. Overall, the information to be gained has important ramifications for understanding etiology and thus contributing to eventual improved intervention and prevention for this costly group of disorders. Notably, understanding of the non-genetic, environmental contribution to disease is expected to increase when genetic factors are identified.
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