Attention-Deficit/Hyperactivity Disorder (AD/HD) is a complex genetic disorder whose clinical presentation is extremely variable. First, within the AD/HD diagnosis, children are subtyped according to the relative distribution of the primary features, resulting in one of three major classifications (i.e., Combined, Predominantly Inattentive, and Predominantly Hyperactive-Impulsive subtypes). Second, children with AD/HD display additional variability in terms of the presence or absence of comorbid externalizing and internalizing psychiatric conditions. Finally, the clinical presentation of AD/HD with respect to subtyping and comorbidity often changes within an individual over time. For example, a child may exhibit primarily hyperactive symptoms in early years and primarily inattentive symptoms later in development. Comorbidity for other psychiatric conditions may emerge or even revert over time, as well. Candidate gene studies and genomic screen analyses have resulted in conflicting conclusions and limited progress in identifying specific genetic factors influencing AD/HD susceptibility. Nearly all studies have defined the phenotype at a single time point according to DSM-IV criteria, without consideration for phenotypic heterogeneity. None of these studies has evaluated the genetic influences on AD/HD etiology while considering developmental changes in subtyping or comorbidity. To the extent that developmental changes in AD/HD subtyping and comorbidity occur, clinical assessments at a single point in time are less likely to capture a child's """"""""true"""""""" diagnostic status. Additionally, by ignoring existing clinical heterogeneity, one loses power to detect genetic effects. Faraone and colleagues (2000) have observed that the sibling recurrence risk (lambdas) for AD/HD increases from 4.0 among AD/HD probands ascertained at a single time point to 17.2 among probands whose AD/HD persists into adolescence, suggesting that the temporal persistence of AD/HD is a """"""""more genetic"""""""" form of the condition. Moreover, the sibling recurrence risk in families with probands that not only have persistence of AD/HD but also comorbid conduct disorder is even higher (lambdas = 26.2) (Faraone et al., 2000). Thus, we should expect to find molecular genetic variation related to the temporal persistence of AD/HD, not only when broadly defined but also when defined in terms of subtyping and comorbidity. To address these developmental changes in AD/HD, we will ascertain 350 AD/HD probands, their parents and all available siblings. Probands and siblings will be clinically evaluated at two time points (once every 2 yrs.) through state-of-the art psychological assessments to capture DSM-IV subtyping categories and comorbid conditions. These clinical data will be used to define more clinically homogeneous subsets of AD/HD families that will then be utilized in candidate gene association analysis of genes involved in neurotransmitter regulation (dopaminergic, serotonergic, noradrenergic systems). In order to identify molecular genetic variation related to these more homogeneous subsets of the AD/HD clinical spectrum, both main gene effects and gene-gene interactions will be considered.
