Molecular Genetics of Inattention in Australia

描述(由申请人提供)：我们最近的研究表明，存在多种遗传独立形式的注意力缺陷/多动障碍(ADHD)，最好单独研究。我们还确定了注意力问题的一个高度可遗传的连续体。这一新应用的长期目标是识别易导致严重注意力不集中问题的遗传因素。这项应用的具体目标是完成全基因组连锁研究和候选基因分析，使用数量性状基因座(QTL)，以及组合连续性状和分类表型定义的多变量方差成分分析。目标样本是澳大利亚的家庭，这些家庭已经被识别和描述为注意力不集中问题(天鹅量表和DSM-IV ADHD症状)。这个双胞胎家庭的样本似乎代表了澳大利亚的总体人口，因此，代表了一种以社区为基础的方法来研究这种形式的ADHD，这种形式的ADHD通常不会引起临床关注。我们将使用新的表型方法，包括注意力不集中的连续评估(Swan量表)和潜伏类定义的ADHD亚型。由于已经收集了两个关键表型的数据，我们将能够从现有的7,550个家系样本中有效地选择最有能力检测连锁或关联的1,200个家系。我们预计有1,000个这样的家庭的完整数据(每个家庭的父母和平均4个兄弟姐妹)。该样本将完成全基因组10厘米扫描，并将对15个有充分记录的候选基因(包括DRD4、DRD5、DAT、SNAP-25和CHRNA4基因)进行单核苷酸多态(SNP)分析。这种结合的方法将确定候选基因与以人群为基础的家庭样本中注意力不集中的ADHD的相关性，并有足够的力量发现与注意力不集中的ADHD有关的新的染色体位置。此外，使用现有的家庭流行病学样本将1)对特定基因与普通人群的相关性提供强大的测试，2)有足够的能力发现与注意力不集中的ADHD相关的新基因座，3)将避免使用临床或基于广告的ADHD病例抽样的其他研究的许多潜在混淆，4)将通过使用独立的和文化多样性的样本来检验来自美国的研究结果的总体相关性。这将显著节省成本，这是因为使用了现有的具有良好特征的样本，以及澳大利亚和美国的调查人员之间合作研究的长期历史。

DESCRIPTION (provided by applicant): Our recent studies have demonstrated the presence of multiple, genetically independent forms of attention deficit/hyperactivity disorder (ADHD) which would be best studied individually. We have also identified a highly heritable continuum of Liability to attention problems. The long-range goal of this new application is the identification of genetic factors that predispose to the development of severe inattention problems. The specific goals of this application are to complete a whole genome linkage study and candidate gene analyses using quantitative trait locus (QTL) as well as multivariate variance components analyses of combined continuous trait and categorical phenotype definitions. The target sample is families in Australia that have already been identified and characterized for inattention problems (SWAN scale and DSM-IV ADHD symptoms). This sample of twin families appears representative of the general population of Australia and, hence, represents a community-based approach to studying this form of ADHD, which frequently does not come to clinical attention. We will use novel phenotyping approaches including a continuum assessment of inattention (the SWAN scale) and latent-class defined ADHD subtypes. Because data on the two key phenotypes have already been collected, we will be in a position to efficiently select the 1,200 families with greatest power to detect linkage or association out of the existing sample of 7,550 families. We anticipate having complete data on 1,000 of these families (both parents and an average of 4 siblings per family). A whole genome 10cM scan will be completed on this sample as will single nucleotide polymorphism (SNP) analysis of 15 well-documented candidate genes (including the DRD4, DRD5, DAT, SNAP-25 and CHRNA4 genes). This combined approach will determine the relevance of candidate genes to inattentive forms of ADHD in a population-based sample of families as well as have sufficient power to discover new chromosomal locations linked to inattentive ADHD. Furthermore, using an existing epidemiological sample of families will 1) provide a powerful test of the relevance of specific genes to the general population, 2) have sufficient power to discover new loci related to inattentive ADHD, 3) will avoid many of the potential confounds of other studies using clinic or advertisement-based sampling of ADHD cases, and 4) will test the general relevance of findings from the United States by the use of an independent and culturally diverse sample. This will be at a marked cost savings due to the employment of existing well-characterized samples and the long history of collaborative studies between investigators from Australia and the United States.