Candidate Gene Analysis of Persistent AD/HD

描述(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，其临床表现极不稳定。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，导致三种主要分类之一(即，组合亚型、主要注意力不集中亚型和主要多动-冲动亚型)。其次，AD/HD儿童在存在或不存在外在性和内在性精神疾病的共病方面表现出额外的变异性。最后，AD/HD在亚型和共病方面的临床表现经常在个体内随着时间的推移而变化。例如，儿童可能在早年主要表现出多动症状，在发育后期主要表现为注意力不集中的症状。随着时间的推移，其他精神疾病的共病也可能出现，甚至复发。候选基因研究和基因组筛选分析在识别影响AD/HD易感性的特定遗传因素方面导致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标准定义了单个时间点的表型，而没有考虑表型的异质性。这些研究都没有评估遗传对AD/HD病因学的影响，同时考虑亚型或合并症的发育变化。就AD/HD亚型和共病的发育变化而言，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，通过忽视现有的临床异质性，一个人失去了检测遗传效应的能力。Faraone和他的同事(2000)已经观察到AD/HD的兄弟姐妹复发风险(Lambdas)从在单个时间点确定的AD/HD先证者中的4.0增加到在AD/HD持续到青春期的先证者中的17.2，这表明AD/HD的时间持续性是这种疾病的一种“更遗传的”形式。此外，在有先证者的家庭中，兄弟姐妹复发的风险甚至更高(lambdas=26.2)(Faraone等人，2000年)。因此，我们应该期待发现与AD/HD的时间持续性相关的分子遗传变异，不仅当广义定义时，而且当根据亚型和共病定义时。为了应对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进行临床评估(每两年一次)。通过最先进的心理评估来捕捉DSM-IV亚型类别和共病情况。这些临床数据将被用来确定更多临床上相同的AD/HD家族亚群，然后用于参与神经递质调节的基因(多巴胺能、5-羟色胺能、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临床谱系中这些更同质的亚组相关的分子遗传变异，将同时考虑主基因效应和基因-基因交互作用。

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.