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，其临床表现极为可变。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分类，从而产生三个主要分类之一（即，组合型、主要注意力不集中型和主要多动冲动亚型）。其次，患有 AD/HD 的儿童在是否存在共病外化和内化精神疾病方面表现出额外的变异性。最后，AD/HD 在亚型和合并症方面的临床表现通常会随着时间的推移在个体中发生变化。例如，儿童可能在早年主要表现出过度活跃的症状，而在发育后期主要表现出注意力不集中的症状。随着时间的推移，其他精神疾病的合并症也可能出现甚至恢复。候选基因研究和基因组筛选分析得出了相互矛盾的结论，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。几乎所有研究都根据 DSM-IV 标准定义了单个时间点的表型，而不考虑表型异质性。这些研究都没有在考虑亚型或合并症的发育变化的同时评估遗传对 AD/HD 病因的影响。如果 AD/HD 亚型和合并症发生发育变化，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，如果忽视现有的临床异质性，人们就会失去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 (lambdas) 从单个时间点确定的 AD/HD 先证者中的 4.0 增加到 AD/HD 持续到青春期的先证者中的 17.2，这表明 AD/HD 的时间持续性是一种“更具遗传性”的疾病形式。此外，在先证者家族中，不仅持续存在AD/HD，而且还患有共病品行障碍，兄弟姐妹的复发风险甚至更高（lambdas = 26.2）（Faraone et al., 2000）。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，而且在亚型和共病方面定义时。为了解决 AD/HD 的这些发育变化，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。先证者和兄弟姐妹将在两个时间点（每两年一次）通过最先进的心理评估进行临床评估，以捕获 DSM-IV 亚型类别和共病状况。这些临床数据将用于定义临床上更同质的 AD/HD 家族子集，然后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）的基因的候选基因关联分析。为了识别与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.