SNP studies in ADHD linked regions

ADHD 相关区域的 SNP 研究

基本信息

批准号：
7761201
负责人：
STANLEY F. NELSON
金额：
$ 50.31万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7761201
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 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 Oligonucleotides Parents Phenotype 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 meetings population based programs therapy development tool transmission process

项目摘要

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）：注意力缺陷多动症（ADHD）是一种普遍的高度遗传性儿童期行为障碍。我们已经在ADHD中进行了第一次粗大基因组扫描（10 cm间距）和精细的映射（<2 cm间距）在269个受影响的兄弟姐妹对（ASP）家族的总样本中，并确定了与16p13和17p11的显着链接。该建议是使用基于测序的方法和常见的SNP基因分型方法来鉴定这些连接区域内的基因中的常见变异和多种稀有突变/多态性，这些区域是ADHD中疾病敏感性的基础。现在，使用高密度SNP键入和大规模的重新方程进行了对这些区域的全面筛选，并采用多组协作方法来测试链接区域中推定的关联的复制，因此可以全面筛选这些区域。为了筛选这两个链接的区域，以促进疾病易感性的常见变体，研究设计是1）屏幕12,000个常见的SNP与310个ASP家族的310个独立三重奏相关联的ADHD； 2）在UCLA收集的另外260个ASP家族中测试推定的SNP协会； 3）测试SNP符合7个单独的ADHD样品的选择标准，包括1934年受影响和2532个对照组。为了测试与多种罕见多态性或突变的关联，将使用来自UCLA ASP家族的90个选定的ADHD影响的高密度寡阵阵列对16p13和17p11进行直接重新配置。在满足显着性阈值的基因上将对其他ADHD影响和对照组进行测序。这些组合方法具有超过80％的能力，可以发现和验证对多动症风险和罕见突变的共同变异贡献。多动症是最常见的儿童行为障碍，对公共卫生有巨大影响。这项工作不仅对ADHD的个人，而且还对社会产生了重大影响，因为数百万学龄儿童受到了多动症的影响，受影响的儿童影响了所有人的课堂学习，并以有时有害的行为继续生活。 ADHD分子基础的识别将使能够开发出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理解，该疾病可能允许制定针对特定遗传因素的干预措施，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基本学习过程的改进。