Candidate Gene Analysis of Persistent AD/HD

描述（由申请人提供）：注意缺陷/多动障碍（AD/HD）是一种复杂的遗传性疾病，其临床表现非常多变。首先，在AD/HD诊断中，根据主要特征的相对分布对儿童进行亚型划分，从而产生三种主要分类之一（即合并型、主要注意力不集中型和主要多动冲动型）。其次，AD/HD患儿在存在或不存在共病的外部性和内部性精神疾病方面表现出额外的可变性。最后，随着时间的推移，AD/HD的临床表现与亚型和合并症有关。例如，儿童可能在早期主要表现为多动症状，在发育后期主要表现为注意力不集中症状。其他精神疾病的合并症也可能随着时间的推移而出现甚至恢复。候选基因研究和基因组筛选分析导致了相互矛盾的结论，并且在确定影响AD/HD易感性的特定遗传因素方面进展有限。几乎所有的研究都是根据DSM-IV标准在单一时间点定义表型，而没有考虑表型异质性。在考虑亚型或合并症的发育变化时，这些研究都没有评估遗传对AD/HD病因的影响。在某种程度上，AD/HD亚型的发育变化和合并症的发生，在单一时间点的临床评估不太可能捕捉到儿童的“真实”诊断状态。此外，由于忽视了现有的临床异质性，人们就失去了检测基因影响的能力。Faraone及其同事（2000）观察到，在单个时间点确定的AD/HD先证中，AD/HD的兄弟姐妹复发风险（lambdas）从4.0增加到持续到青春期的AD/HD先证中的17.2，这表明AD/HD的时间持续性是一种“更多的遗传”形式。此外，在先证家族中，既存在AD/HD持续性，又存在共病行为障碍的兄弟姐妹复发风险更高（lambdas = 26.2） （Faraone et al., 2000）。因此，我们应该期望发现与AD/HD的时间持久性相关的分子遗传变异，不仅在广义上定义，而且在亚型和合并症方面定义。为了解决AD/HD的这些发育变化，我们将确定350个AD/HD先证，他们的父母和所有可用的兄弟姐妹。先证和兄弟姐妹将在两个时间点（每2年一次）通过最先进的心理评估进行临床评估，以捕获DSM-IV亚型类别和合并症。这些临床数据将用于定义更多临床同质的AD/HD家族亚群，然后将用于参与神经递质调节（多巴胺能、血清素能、去甲肾上腺素能系统）的候选基因关联分析。为了确定与AD/HD临床谱中这些更均匀的亚群相关的分子遗传变异，将考虑主要基因效应和基因相互作用。

DESCRIPTION (provided by applicant): 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.