Candidate Gene Analysis of Persistent AD/HD

描述（由申请人提供）：注意力缺陷/多动障碍（AD/HD）是一种复杂的遗传性疾病，其临床表现极其多变。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，从而产生三种主要分类之一（即，组合型、主要注意力不集中型和主要多动-冲动型亚型）。其次，AD/HD儿童在是否存在共病的外化和内化精神疾病方面显示出额外的变异性。最后，随着时间的推移，AD/HD的亚型和合并症的临床表现往往会在个体内发生变化。例如，一个孩子可能在早年表现出主要的多动症状，在发育后期表现出主要的注意力不集中症状。其他精神疾病的合并症也可能出现，甚至随着时间的推移而恢复。候选基因研究和基因组筛选分析在确定影响AD/HD易感性的特定遗传因素方面产生了相互矛盾的结论和有限的进展。几乎所有的研究都根据DSM-IV标准在单个时间点定义了表型，而没有考虑表型异质性。这些研究都没有评估遗传因素对AD/HD病因的影响，同时考虑亚型或合并症的发育变化。在AD/HD亚型和合并症发生发展变化的程度上，在单个时间点的临床评估不太可能捕获儿童的“真实”诊断状态。此外，由于忽略了现有的临床异质性，人们失去了检测遗传效应的能力。Faraone及其同事（2000）观察到AD/HD的兄弟姐妹复发风险从单个时间点确定的AD/HD先证者的4.0增加到AD/HD持续到青春期的先证者的17.2，表明AD/HD的时间持续性是该疾病的“更多遗传”形式。此外，不仅具有AD/HD的持续性，而且具有共病行为障碍的先证者的家族中的兄弟姐妹复发风险甚至更高（fraidas = 26.2）（Faraone等人，2000年）。因此，我们应该期望找到与AD/HD的时间持续性相关的分子遗传变异，不仅在广义上定义时，而且在亚型和共病方面定义时。为了解决AD/HD的这些发展变化，我们将确定350名AD/HD先证者，他们的父母和所有可用的兄弟姐妹。先证者和同胞将在两个时间点进行临床评价（每2年一次）。通过最先进的心理评估来捕获DSM-IV亚型类别和共病状况。这些临床数据将用于定义AD/HD家族的临床同质子集，然后将其用于参与神经递质调节（多巴胺能、多巴胺能、去甲肾上腺素能系统）的基因的候选基因关联分析。为了鉴定与AD/HD临床谱的这些更同质子集相关的分子遗传变异，将考虑主要基因效应和基因-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.