SNP studies in ADHD linked regions

描述(申请人提供)：注意缺陷多动障碍(ADHD)是一种常见的高度遗传性儿童期发病的行为障碍。我们在269个受影响的同胞对(ASP)家系样本中进行了第一次全基因组粗略扫描(间距10 cM)和精细作图(感兴趣区间距2 cM)，发现与16p13和17p11有显著连锁。这项建议是使用基于测序的方法和常见的SNP基因分型方法来识别这些连锁区域内的常见变异和多个罕见突变/多态，这些区域是ADHD疾病易感性的基础。受ADHD影响的同胞对(ASP)大样本的可获得性和现代基因组学的工具现在使得使用高密度SNP分型和大规模重新测序来全面筛选这些区域变得可行，并采取了多组合作的方法来测试假设的关联在关联区域中的复制。为了筛选这两个连锁区域中导致疾病易感性的常见变异，研究设计是：1)在来自310个ASP家系的310个独立三组中筛选12,000个与ADHD相关的常见SNP；2)在加州大学洛杉矶分校收集的另外260个ASP家系中测试假定的SNP关联；3)在7个单独的ADHD样本上测试符合选择标准的SNP，这些样本总共包括1934名受影响者和2532名对照。为了测试与多种罕见的多态或突变的相关性，将使用高密度寡核苷酸阵列对来自加州大学洛杉矶分校的ASP家系的90名ADHD患者进行16p13和17p11上的基因直接重测序。其他受ADHD影响的患者和对照将在符合显著阈值的基因上进行测序。这些组合方法有超过80%的能力来发现和验证导致ADHD风险的常见变异和罕见的突变。ADHD是儿童时期最常见的行为障碍，对公众健康有很大影响。 这项工作不仅对ADHD患者个人有重大影响，而且对社会也有重大影响，因为数百万学龄儿童患有ADHD，受影响的儿童影响所有人的课堂学习，并继续他们的生活，有时会有有害的行为。识别ADHD的分子基础将使开发更好的诊断工具来诊断ADHD及其遗传亚型。风险基因的知识提供了对疾病的了解，从而可以开发针对特定遗传因素的干预措施，并能够重点探索可能影响表型表达的环境因素。此外，识别与行为有明确关系的基因将有助于更好地理解学习的基本过程。

DESCRIPTION (provided by applicant): Attention Deficit Hyperactivity Disorder (ADHD) is a common highly heritable childhood-onset behavioral disorder. We have performed the first coarse genome-wide scans (10 cM spacing) and fine mapping (<2 cM spacing in regions of interest) in ADHD in a total sample of 269 affected sibling pair(ASP) families and identified significant linkage to 16p13 and 17p11. This proposal is to use sequencing based approaches and common SNP genotyping approaches to identify both common variants and multiple rare mutations/polymorphisms in genes within these linked regions that underlie disease susceptibility in ADHD. The availability of a large ADHD Affected Sibling Pair (ASP) sample and the tools of modern genomics now make comprehensive screening of these regions practical using high density SNP typing and large scale resequencing, and a multi-group collaborative approach is taken for testing replication of putative associations in the linked regions. In order to screen these two linked regions for common variants contributing to disease susceptibility, the Research Design is to 1) Screen 12,000 common SNPs for association with ADHD in 310 independent trios from 310 ASP families; 2) Test putative SNP associations in an additional 260 ASP families collected at UCLA; 3) Test SNPs meeting selection criteria on 7 separate ADHD samples consisting in total of 1934 affecteds and 2532 controls. In order to test for association with multiple rare polymorphisms or mutations, direct resequencing of genes on 16p13 and 17p11 will be performed using high density oligo arrays on 90 selected ADHD affecteds from the UCLA cohort of ASP families. Additional ADHD affecteds and controls will be sequenced at genes meeting significance thresholds. These combined approaches have over 80% power to discover and validate common variant contributions to ADHD risk and rare mutations. ADHD is the most commonly diagnosed behavioral disorder of childhood and has a dramatic effect on public health. This work has a significant impact on not only the individual with ADHD but also society, as millions of school aged children are affected with ADHD and affected children impact classroom learning for all, as well continue through their lives with sometimes deleterious behaviors. Identification of the molecular basis of ADHD will enable better diagnostic tools to be developed to diagnose ADHD and its genetic subtypes. Knowledge of risk genes provides an understanding of the disorder that may allow for the development of interventions tailored to the specific genetic factors, as well as enable focused exploration of environmental factors that might impact on expression of the phenotype. Additionally, identification of genes with clear relationships to behavior will provide an improved understanding of basic processes of learning.