SNP studies in ADHD linked regions

描述（由申请人提供）：注意缺陷多动障碍（ADHD）是一种常见的高度遗传性儿童期行为障碍。我们对269个受影响的兄弟姐妹（ASP）家族进行了首次粗全基因组扫描（间隔10厘米）和精细定位（兴趣区域间隔<2厘米），并确定了与16p13和17p11的显著联系。该建议是使用基于测序的方法和常见SNP基因分型方法来识别ADHD疾病易感性基础上这些相关区域内基因的常见变异和多种罕见突变/多态性。大量ADHD影响兄弟姐妹对（ASP）样本的可用性和现代基因组学工具现在使得使用高密度SNP分型和大规模重测序对这些区域进行全面筛选成为可能，并且采用多组协作方法来测试关联区域中假定关联的复制。为了筛选这两个关联区域中导致疾病易感性的常见变异，研究设计是：1)在310个ASP家族的310个独立三人组中筛选与ADHD相关的12,000个常见snp；2)在加州大学洛杉矶分校收集的另外260个ASP家族中测试假定的SNP关联；3)在7个单独的ADHD样本（共1934名受影响者和2532名对照组）上测试符合选择标准的snp。为了测试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90名来自加州大学洛杉矶分校ASP家族队列的ADHD患者进行16p13和17p11基因的直接重测序。其他ADHD患者和对照组将在符合显著性阈值的基因上进行测序。这些综合方法有超过80%的能力发现和验证共同变异对ADHD风险和罕见突变的贡献。多动症是儿童时期最常见的行为障碍，对公众健康有着巨大的影响。

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.