Molecular Epidemiology of Inattentive ADHD

描述（由申请人提供）： 这项申请要求5年的资金，以确定易导致注意力缺陷/多动障碍（ADHD）发展和过程的遗传因素。以前，我们使用了出生记录为基础的双胞胎设计，以调查ADHD表型的哪些元素是可遗传的，并确定潜在的遗传性的性质是否代表一个连续的功能障碍或离散的临床实体的存在。我们已经确定了一种高度遗传的注意力不集中的ADHD形式，与显著的学术和社会问题相关，这在男孩和女孩中都很常见，在临床人群和正在进行的ADHD遗传连锁研究中代表性不足。这一发现表明，新的采样策略将是必要的，以确定基因有助于这种常见形式的注意力障碍的病因。我们建议把重点放在确定受影响的和不和谐的兄弟姐妹对大家庭与特定类型的父母确定的注意力问题，使用出生记录为基础的样本的家庭有4个或更多的兄弟姐妹。使用这个新招募的样本和我们现有的双胞胎为基础的家庭样本，我们将应用最先进的实验室和分析方法来完成一个基因组调查的特定染色体位点的连锁注意力不集中的问题。我们的目标是招募450对受影响的兄弟姐妹，他们都有严重的纯注意力问题，还有1,000对不和谐的兄弟姐妹。使用非参数连锁方法，我们将完成一个平均间距为10厘米的微卫星重复标记的基因组调查，以确定与此表型相关的染色体区域。我们将尝试进一步完善的位置，推定的连锁位置使用定量和多元连锁的方法。该应用程序的独特功能包括经过充分测试的2阶段人群抽样方法，用于家庭识别，重点关注男孩和女孩中常见的高度遗传性注意力不集中的ADHD亚型，该亚型在临床和当前基因分型样本中代表性不足，以及通过使用注意力不集中的ADHD人群样本来测试任何发现的普遍性的能力。我们注意到，这种受影响的同胞对样本也将是理想的，在未来的研究中进行更集中的神经影像学，神经心理学性能和神经生理功能的研究。

DESCRIPTION (provided by applicant): This application is a request for 5 years of funding to identify genetic elements which predispose to the development and course of attention deficit/hyperactivity disorder (ADHD). Previously we have used a birth records-based twin design to investigate what elements of the ADHD phenotype are heritable and to determine whether the nature of the underlying heritability represents a continuum of dysfunction or the presence of discrete clinical entities. We have identified a highly heritable form of inattentive ADHD associated with marked academic and social problems which is common in both boys and girls and which is underrepresented in clinic-based populations and ongoing genetic linkage studies of ADHD. This finding suggests that new sampling strategies will be necessary to identify genes contributing to the etiology of this common form of attention disorders. We propose to focus on ascertaining affected and discordant sibling pairs from large families with specific types of parent identified attention problems using a birth records-based sample of families with 4 or more siblings. Using this newly recruited sample and our existing sample of twin-based families we will apply state-of-the-art laboratory and analytic methods to complete a genomic survey for linkage of particular chromosomal loci to inattention problems. Our goal is to recruit a total of 450 affected sibling pairs which both have a severe form of pure attention problems and 1,000 sibling pairs who are discordant. Using non-parametric linkage methods we will complete a genomic survey of microsatellite repeat markers with an average spacing of 10 cM to identify chromosomal regions associated with this phenotype. We will try to further refine the location of putative linkage locations using quantitative and multivariate linkage approaches. The unique features of this application include a fully tested 2-stage population sampling approach for family identification, a focus on a highly heritable inattentive subtype of ADHD common in boys and girls which is underrepresented in clinical and current genotyping samples and the ability to test the generalizability of any findings by the use of population samples of inattentive ADHD. We note that this affected sib-pair sample would also be ideal to conduct more focused studies of neuroimaging, neuropsychological performance, and neurophysiological functioning in future studies.