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作的行为障碍。我们在269个受影响的兄弟姐妹对（ASP）家庭的总样本中进行了ADHD的第一次粗略的全基因组扫描（10 cM间距）和精细定位（感兴趣区域<2 cM间距），并确定了与16 p13和17 p11的显着连锁。该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关联区域内的基因中的常见变异和多个罕见突变/多态性，这些区域是ADHD疾病易感性的基础。一个大的ADHD受影响的兄弟姐妹对（ASP）的样本和现代基因组学的工具的可用性，现在使这些地区的全面筛选实际使用高密度SNP分型和大规模的重测序，和多组协作的方法被用来测试复制的推定关联的链接区域。为了筛选这两个相关区域中与疾病易感性相关的常见变异，研究设计是：1）在来自310个ASP家族的310个独立三人组中筛选12，000个与ADHD相关的常见SNP; 2）在UCLA收集的另外260个ASP家族中测试推定的SNP关联; 3）在7个单独的ADHD样本上测试符合选择标准的SNP，所述样本包括总共1934个受影响者和2532个对照。为了检测与多种罕见多态性或突变的关联，将使用高密度寡核苷酸阵列对来自UCLA ASP家族队列的90名选定ADHD患者进行16 p13和17 p11基因的直接重测序。额外的ADHD受影响者和对照者将在满足显著性阈值的基因处进行测序。这些组合方法有超过80%的能力发现和验证常见变异对ADHD风险和罕见突变的贡献。ADHD是儿童期最常见的行为障碍，对公共健康有着巨大的影响。 这项工作不仅对ADHD患者产生了重大影响，而且对社会也产生了重大影响，因为数百万学龄儿童受到ADHD的影响，受影响的儿童影响了所有人的课堂学习，并在他们的生活中继续进行有时有害的行为。ADHD的分子基础的鉴定将使更好的诊断工具，以诊断ADHD及其遗传亚型。风险基因的知识提供了对疾病的理解，这可能允许针对特定遗传因素制定干预措施，并能够集中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提供对学习基本过程的更好理解。

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.