Searching for ADHD Susceptibility Genes

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DESCRIPTION (provided by the applicant): Attention Deficit Hyperactivity Disorder (ADHD) is a common disorder of childhood associated with school failure, psychiatric co-morbidity and psychosocial disability. Because family and twin studies suggest that ADHD has a substantial genetic component, several research groups have now begun molecular genetic studies of the disorder. Unlike other psychiatric conditions, which have produced an array of conflicting results, molecular genetic research into ADHD has produced a body of work implicating four genes in the etiology of the disorder: DRD4, DAT, DRD5 and 5HTlB. We have chosen these genes, because meta-analyses of extant association studies suggest they mediate susceptibility to ADHD. They are also implicated by their relevance to other neurobiologic studies, implicating monoamine pathways in the etiology of the disorder. Although these four genes have been implicated in ADHD, susceptibility variants with known functional significance have not yet been identified. The goal of the present proposal is to identify such variants and their implications. We have two main aims: First, using sib-pair and family-based association study designs, we will search for variants of the DRD4, DAT, DRD5 and 5HTlB genes, which increase susceptibility to ADHD. Second, we will test the hypothesis that the gene variants, which predispose to ADHD, also predict greater persistence and adverse outcomes among ADHD children and their siblings. The data available for the proposed have been, or are in the process of being, collected by the PI, with separate NIH funding (R01HD37694, R01HD37999). One study is a sib-pair linkage study, which is collecting 1,200 subjects from 300 sib-pair families identified through a Persistent DSM-IV ADHD proband. The second study builds upon two longitudinal family studies of ADHD. These studies will yield 243 nuclear families suitable for family-based association studies. The linkage study and the longitudinal family studies use the same clinical data collection protocols.