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基因独立形式的注意力缺陷/多动障碍（ADHD），最好是单独研究。我们还确定了注意力问题的高度可遗传的连续性。这项新应用的长期目标是确定易导致严重注意力不集中问题发展的遗传因素。本应用程序的具体目标是完成全基因组连锁研究和候选基因分析，使用数量性状位点（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已经确定并具有注意力不集中问题特征的家庭（SWAN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一般人群，因此，代表了以社区为基础的方法来研究这种形式的多动症，这通常不会引起临床注意。我们将使用新的表现型方法，包括对注意力不集中的连续评估（SWAN量表）和潜在类别定义的ADHD亚型。由于已经收集了两种关键表型的数据，我们将能够有效地从现有的7550个家族样本中选择出1200个最有能力检测连锁或关联的家族。我们预计将有1000个这样的家庭的完整数据（双亲和平均每个家庭有4个兄弟姐妹）。将对该样本进行全基因组10cM扫描，并对15个已证实的候选基因（包括DRD4、DRD5、DAT、SNAP-25和CHRNA4基因）进行单核苷酸多态性（SNP）分析。这种结合的方法将在基于人群的家庭样本中确定候选基因与注意力不集中形式多动症的相关性，并有足够的能力发现与注意力不集中多动症相关的新染色体位置。此外,使用现有的流行病学的家庭样本1)将提供一个强大的测试的特定基因的相关性一般人群中,2)有足够的权力来发现新的基因座与漫不经心多动症,3)将避免许多其他研究的潜在混淆使用诊所或advertisement-based抽样多动症的情况下,和4)将测试的总体相关性发现使用一个独立的和美国的多元文化。由于采用现有的特征良好的样本以及澳大利亚和美国研究人员之间长期的合作研究历史，这将显著节省成本。

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.