Candidate Gene Analysis of Persistent AD/HD

持续性 AD/HD 候选基因分析

• 批准号: 6812045
• 负责人: ALLISON E ASHLEY-KOCH
• 金额: $ 61.16万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6812045
• 关键词: Internet; attention deficit disorder; behavioral /social science research tag; child psychology; clinical research; comorbidity; data collection; disease /therapy duration; family genetics; gene expression; gene interaction; genetic disorder; genetic mapping; genetic markers; genetic screening; genetic susceptibility; genotype; human subject; longitudinal human study; mental disorder diagnosis; middle childhood (6-11); neurotransmitter transport; relapse /recurrence; siblings; single nucleotide polymorphism

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.

描述（由申请人提供）：注意力缺陷/多动症（AD/HD）是一种复杂的遗传疾病，其临床表现非常可变。首先，在AD/HD诊断中，根据主要特征的相对分布将儿童亚型亚型，从而导致三种主要分类之一（即组合，主要不专心，主要是多动激动的亚型）。其次，AD/HD的儿童在存在或不存在合并症外在化和内在化精神病状态方面显示出额外的可变性。最后，随着时间的流逝，AD/HD相对于亚型和合并症的临床表现通常会发生变化。例如，儿童可能在早期主要表现出多动态症状，并且主要在发育后主要出现不专心的症状。其他精神病疾病的合并症也可能随着时间的流逝而出现甚至恢复。候选基因研究和基因组筛查分析导致结论矛盾，并且在识别影响AD/HD敏感性的特定遗传因素方面的进展有限。几乎所有研究都根据DSM-IV标准在一个时间点上定义了表型，而无需考虑表型异质性。这些研究都没有评估对AD/HD病因的遗传影响，同时考虑了亚型或合并症的发展变化。如果发生AD/HD亚型和合并症的发育变化，则单点的临床评估不太可能捕获孩子的“真实”诊断状态。另外，通过忽略现有的临床异质性，人们失去了检测遗传作用的能力。 Faraone及其同事（2000年）已经观察到，AD/HD的兄弟姐妹复发风险（Lambdas）从一个时间点确定的AD/HD Probands中的4.0增加到17.2，其AD/HD持续到青春期中的Probands中，表明AD/HD的临时效率更高，这是一种属性。此外，患有概率的家庭的兄弟姐妹复发风险不仅具有AD/HD的持久性，而且合并症的行为障碍甚至更高（Lambdas = 26.2）（Faraone等，2000）。因此，我们应该期望找到与AD/HD的时间持久性相关的分子遗传变异，不仅在广泛定义时，而且还以亚型和合并症的方式定义时。为了解决AD/HD中的这些发展变化，我们将确定350 AD/HD Probands，他们的父母和所有可用的兄弟姐妹。检验和兄弟姐妹将通过最先进的心理评估在两个时间点（每2年一次）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AD/HD家族的更临床均匀的子集，然后将其用于候选基因关联分析，用于与神经递质调节（多巴胺能，羟色胺能，羟色胺能，异义肾上腺素能系统）的基因分析。为了鉴定与AD/HD临床谱的这些更均匀的亚集有关的分子遗传变异，将考虑主要基因效应和基因基因相互作用。