Molecular Genetics of Inattention in Australia

澳大利亚注意力不集中的分子遗传学

• 批准号: 6924979
• 负责人: RICHARD D TODD
• 金额: $ 56.18万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-25 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6924979
• 关键词: Australia; attention deficit disorder; behavioral /social science research tag; behavioral genetics; clinical research; family genetics; human subject; linkage mapping; mental disorder diagnosis; mental health epidemiology; patient oriented research; quantitative trait loci

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.

描述（由申请人提供）：我们最近的研究表明，存在多种遗传上独立的注意力缺陷/多动障碍（ADHD），最好单独研究。我们还发现了一个高度遗传的连续性注意力问题的责任。这项新应用的长期目标是识别导致严重注意力不集中问题的遗传因素。本申请的具体目标是使用数量性状位点（QTL）以及组合连续性状和分类表型定义的多变量方差分量分析来完成全基因组连锁研究和候选基因分析。目标样本是澳大利亚已经确定和表征注意力不集中问题（SWAN量表和DSM-IV ADHD症状）的家庭。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，代表了一种以社区为基础的方法来研究这种形式的ADHD，这种形式通常不会引起临床的注意。我们将使用新的表型分析方法，包括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。由于已经收集了两个关键表型的数据，我们将能够从现有的7,550个家庭样本中有效地选择1,200个具有最大能力检测连锁或关联的家庭。我们预计有1,000个家庭的完整数据（每个家庭有父母和平均4个兄弟姐妹）。将对该样本进行全基因组10 cM扫描，并对15个已充分记录的候选基因（包括DRD 4、DRD 5、DAT、SNAP-25和CHRNA 4基因）进行单核苷酸多态性（SNP）分析。这种结合的方法将确定候选基因与基于人群的家庭样本中注意力不集中的ADHD形式的相关性，并有足够的能力发现与注意力不集中的ADHD相关的新染色体位置。此外，使用现有的家庭流行病学样本将1）提供特定基因与一般人群相关性的强有力的测试，2）具有足够的能力来发现与注意力不集中的ADHD相关的新基因座，3）将避免使用ADHD病例的临床或基于实验的采样的其他研究的许多潜在混淆，4）将通过使用独立和文化多样性的样本来测试来自美国的调查结果的一般相关性。由于采用了现有的特征良好的样品，以及澳大利亚和美国的调查人员之间长期合作研究的历史，这将显著节省费用。