Quantifying the impact of rare mutations on ADHD

量化罕见突变对多动症的影响

基本信息

批准号：
8471783
负责人：
Benjamin Michael Neale
金额：
$ 56.49万
依托单位：
BROAD INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8471783
关键词：
Adult Attention Attention deficit hyperactivity disorder Autistic Disorder Bioinformatics Biological Biological Assay Biological Process California Child Childhood Code Collaborations Collection Commit Communities Comorbidity DNA DSM-IV Data Data Analyses Databases Deposition Diagnosis Disease Enrollment Ensure Etiology European Failure Family Family Study Functional disorder Funding Gene Frequency General Hospitals Genes Genetic Genetic Variation Genotype Health Care Costs Heritability Human Human Genome Inherited Institutes International Joints Letters Light Los Angeles Massachusetts Medical Meta-Analysis Molecular Molecular Genetics Mutation Nature Occupational Outcome Parents Pathway interactions Patients Pharmaceutical Preparations Play Population Preventive Protocols documentation Regulation Research Research Personnel Risk Risk Factors Role Sample Size Sampling Schizophrenia Schools Secure Single Nucleotide Polymorphism Societies Subgroup Substance abuse problem Susceptibility Gene Technology Testing Time Traffic accidents Twin Studies United States National Institutes of Health Universities Variant Work base case control cohort cost cost effective database of Genotypes and Phenotypes disability exome exome sequencing family genetics follow-up genetic linkage analysis genome sequencing genome wide association study genome-wide genome-wide linkage health care service utilization health economics improved innovation insight meetings prevent proband psychosocial research study sample collection tool

项目摘要

DESCRIPTION (provided by applicant): The technological revolution in genetics is beginning to yield results for ADHD. Rare copy number variants have been identified that confer risk to ADHD providing the first molecular evidence for risk to the disease. In contrast, genome-wide association studies of single nucleotide polymorphisms (SNPs), to date, have yet to unequivocally identify risk factors that predisposes to ADHD with the most recent meta-analysis totaling 2,064 trios, 896 cases and 2,455 controls. This lack of progress stands in stark contrast to the strong evidence for heritability of ADHD, attention and activity levels from twin and family studies. Among the several possible explanations for this disconnect is that rare SNPs confer risk to ADHD. Given that rare CNVs clearly play a role in the pathophysiology of ADHD, it is not unreasonable to expect that rare SNPs of large effect may also exist. We are proposing the first study to comprehensively define the role of rare SNPs drawn from the coding region of genes in the etiology of the disorder. We will do so by using the newly developed exome chip, an innovative, cost-effective technology that will allow us to assay approximately 200,000 rare SNPs found in the coding region of the human genome. This exome chip assay should capture nearly all SNPs at an allele frequency threshold of 0.1% in European populations and captures an estimated 80% of the variants with an allele frequency of 0.02%. Our specific aims are: Aim 1: Assay Rare Variation in 1,800 ADHD Trios. We will generate exome chip data on a total of 1,800 ADHD trio families to identify rare functional inherited variation that predisposes to ADHD. We will assay approximately 200,000 rare SNP mutations in the exome. Aim 2: Comprehensively Analyze the Identified Rare Variation. Upon completion of the genotyping assays, we will perform single-locus and regional association analysis of the exome chip data. We will then extend these primary analyses by interrogating genes and pathways by leveraging bioinformatics tools to improve the power to detect genes and to more clearly interpret our primary results. Aim 3: Share All Data with the Scientific Community. We are committed to ensuring that all data generated by this application will be deposited in dbGaP and any other database required by NIH regulations. Upon completing this project, we expect to provide the field with a treasure trove of rare DNA variants that can be followed up with functional, biologica assays. This work is significant because ADHD is a common disorder of childhood associated with school failure, psychiatric comorbidity and psychosocial disability in childhood. Most cases persist into adulthood when the disorder is additionally associated with occupational failure, criminality, traffic accidents, substance abuse and increased medical health care utilization. Health economic studies suggest that, in adulthood, the cost of ADHD to society is between $77.5 and $115.9 billion each year. Current treatments are only partially effective, and no preventive treatments exist. New treatment targets are needed to develop better medications for treating ill patients and, perhaps, for preventing the disorder in susceptible people.

描述（由申请人提供）：遗传学的技术革命开始产生多动症的结果。已经确定了罕见的拷贝数变体，赋予多动症的风险提供第一个分子证据证明疾病风险。相比之下，迄今为止，单核苷酸多态性（SNP）的全基因组关联研究尚未明确地识别易于多动症的危险因素与最新的荟萃分析，总计为2,064个三重奏，896例和2,455例对照。这种缺乏进步与多动症，双胞胎和家庭活动水平的遗传力的有力证据形成鲜明对比研究。在这种断开连接的几种可能的解释中，罕见的SNP赋予多动症风险。鉴于罕见的CNV显然在ADHD的病理生理学中发挥了作用，因此期望也可能存在罕见的巨大效果SNP并不是不合理的。我们提出了第一项研究，以全面定义从基因编码区域中稀有的SNP在该疾病病因中的作用。我们将通过使用新开发的外显子芯片（一种创新的，具有成本效益的技术，它将使我们能够测定在人类基因组的编码区域中发现的约200,000个稀有SNP。该外显子芯片测定法应在欧洲人群中以0.1％的等位基因频率阈值捕获几乎所有SNP，并捕获估计有80％的变体，等位基因频率为0.02％。我们的具体目的是：AIM 1：在1,800 ADHD Trios中测定罕见变化。我们将生成总共1,800个ADHD三重奏家族的外显子芯片数据，以识别易于多动症的罕见功能遗传变异。我们将在外显子中测定约200,000个稀有SNP突变。 AIM 2：全面分析确定的罕见变化。基因分型测定完成后，我们将对外显子芯片数据进行单位核心和区域关联分析。然后，我们将通过利用生物信息学工具来提高检测基因的能力并更清楚地解释我们的主要结果来扩展这些主要分析。目标3：与科学界共享所有数据。我们致力于确保该应用程序生成的所有数据都将存放在DBGAP以及NIH法规所需的任何其他数据库中。完成该项目后，我们期望为该领域提供稀有DNA变体的宝库，可以进行功能性的生物学测定。这项工作很重要，因为多动症是儿童失败，精神病合并症和儿童心理残疾的常见疾病。当该疾病还与职业失败，犯罪，交通事故，滥用药物和增加医疗保健利用相关时，大多数病例一直持续到成年。卫生经济研究表明，在成年后，社会的多动症成本在每年77.5至1159亿美元之间。当前的治疗仅是部分有效的，并且没有预防治疗。需要新的治疗目标来开发更好的治疗患者的药物，也许可以预防易感人群的疾病。