SNP studies in ADHD linked regions

ADHD 相关区域的 SNP 研究

• 批准号: 7481684
• 负责人: STANLEY F. NELSON
• 金额: $ 5.45万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7481684
• 关键词: 16p; 17p; Accounting; Affect; Alleles; Amino Acids; Area; Attention deficit hyperactivity disorder; Base Sequence; Behavior; Behavior Disorders; Biological Assay; Blood capillaries; Boston; Child; Childhood; Chromosome Mapping; Code; Collection; Colombia; Custom; DNA; DNA Resequencing; Depth; Diagnosis; Diagnostic; Disease; Disease susceptibility; Environmental Risk Factor; Exons; Family; Finland; Gene Frequency; Genes; Genetic; Genetic Polymorphism; Genomics; Genotype; Haplotypes; Heterozygote; Individual; Knowledge; Learning; Life; Link; Linkage Disequilibrium; Los Angeles; Maps; Methods; Molecular; Mutation; National Institute of Mental Health; Netherlands; Nonsense Mutation; Numbers; Oligonucleotides; Parents; Phenotype; Polymerase Chain Reaction; Population; Predisposition; Process; Promoter Regions; Public Health; Research Design; Research Personnel; Risk; Sample Size; Sampling; School-Age Population; Screening procedure; Selection Criteria; Siblings; Single Nucleotide Polymorphism; Societies; Surveys; Testing; Validation; Variant; Work; base; capillary; cohort; density; design; disorder risk; follow-up; genome wide association study; improved; interest; programs; therapy development; tool; transmission process

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.

描述（由申请人提供）：注意力缺陷多动障碍（ADHD）是一种常见的高度遗传性儿童期发病的行为障碍。我们对 ADHD 的 269 个受影响的兄弟姐妹对 (ASP) 家族的总样本进行了首次粗基因组范围扫描（10 cM 间距）和精细定位（感兴趣区域<2 cM 间距），并确定了与 16p13 和 17p11 的显着关联。该提案旨在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基因的常见变异和多种罕见突变/多态性，这些区域是 ADHD 疾病易感性的基础。现在，大量 ADHD 受影响的兄弟姐妹对 (ASP) 样本的可用性和现代基因组学工具使得使用高密度 SNP 分型和大规模重测序对这些区域进行全面筛选变得可行，并且采用多组协作方法来测试链接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 家族中测试假定的 SNP 关联； 3) 在 7 个单独的 ADHD 样本（总共包括 1934 名受影响者和 2532 名对照者）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来自 UCLA ASP 家族队列的 90 名选定的 ADHD 患者进行 16p13 和 17p11 基因的直接重测序。其他 ADHD 受影响者和对照者将在满足显着性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 ADHD 风险的常见变异和罕见突变。 ADHD 是最常见的儿童行为障碍，对公共健康产生巨大影响。 这项工作不仅对患有多动症的个人而且对社会产生重大影响，因为数百万学龄儿童受到多动症的影响，受影响的儿童影响所有人的课堂学习，并在他们的生活中继续有时做出有害的行为。鉴定 ADHD 的分子基础将有助于开发更好的诊断工具来诊断 ADHD 及其遗传亚型。对风险基因的了解可以帮助我们了解疾病，从而可以制定针对特定遗传因素的干预措施，并可以集中探索可能影响表型表达的环境因素。此外，识别与行为具有明确关系的基因将有助于更好地理解学习的基本过程。