Molecular Epidemiology of Inattentive ADHD

描述(由申请人提供)： 这项申请是一项为期5年的资金申请，以确定易导致注意力缺陷/多动障碍(ADHD)发展和病程的遗传因素。此前，我们使用了基于出生记录的双胞胎设计来研究ADHD表型的哪些元素是可遗传的，并确定潜在遗传性的性质是否代表了功能障碍的连续体或离散临床实体的存在。我们发现了一种高度可遗传的注意力不集中的ADHD形式，与显著的学术和社会问题有关，这种形式在男孩和女孩中都很常见，在以临床为基础的人群和正在进行的ADHD遗传连锁研究中没有得到很好的表现。这一发现表明，新的抽样策略将是必要的，以确定这种常见形式的注意力障碍的病因学基因。我们建议使用基于出生记录的有4个或更多兄弟姐妹的家庭样本，重点确定具有特定父母类型的注意力问题的大家庭中受影响的和不和谐的兄弟姐妹对。利用这个新招募的样本和我们现有的双胞胎家庭样本，我们将应用最先进的实验室和分析方法来完成一项基因组调查，以确定特定染色体座位与注意力不集中问题的联系。我们的目标是招募总共450对受影响的兄弟姐妹，他们都有严重的纯注意力问题，以及1000对不和谐的兄弟姐妹。使用非参数连锁方法，我们将完成平均间距为10 cM的微卫星重复标记的基因组调查，以确定与该表型相关的染色体区域。我们将尝试使用定量和多变量连锁方法进一步细化假定连锁位置的位置。该应用程序的独特功能包括用于家庭鉴定的全面测试的两阶段人口抽样方法，重点关注在男孩和女孩中常见的高度可遗传的注意力不集中的ADHD亚型，该亚型在临床和当前的基因分型样本中未得到充分代表，以及能够通过使用注意力不集中ADHD的人口样本来测试任何发现的概括性。我们注意到，这个受影响的同胞对样本也将是在未来的研究中进行更有针对性的神经成像、神经心理表现和神经生理功能研究的理想选择。

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.