Quantifying the impact of rare mutations on ADHD

量化罕见突变对多动症的影响

• 批准号: 8664000
• 负责人: Benjamin Michael Neale
• 金额: $ 17.6万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 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/8664000
• 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

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）：遗传学技术革命正在开始为多动症带来成果。罕见的拷贝数变异已被鉴定出，这些变异会带来 ADHD 的风险，为该疾病的风险提供了第一个分子证据。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确定易患 ADHD 的危险因素，最新的荟萃分析总计 2,064 个三人组、896 个病例和 2,455 个对照。这种缺乏进展与多动症遗传性、双胞胎和家庭的注意力和活动水平的有力证据形成鲜明对比 研究。对于这种脱节的几种可能的解释是，罕见的 SNP 会带来 ADHD 的风险。鉴于罕见的 CNV 显然在 ADHD 的病理生理学中发挥着作用，因此可以合理地预期，罕见的具有大作用的 SNP 也可能存在。我们正在提出第一项研究，以全面定义从基因编码区提取的稀有 SNP 在疾病病因学中的作用。我们将通过使用新开发的外显子组芯片来实现这一目标，这是一种创新的、具有成本效益的技术，使我们能够分析人类基因组编码区域中发现的大约 200,000 个稀有 SNP。该外显子组芯片检测应捕获欧洲人群中等位基因频率阈值为 0.1% 的几乎所有 SNP，并捕获等位基因频率为 0.02% 的估计 80% 的变异。我们的具体目标是： 目标 1：检测 1,800 个 ADHD 三人组中的罕见变异。我们将生成总共 1,800 个 ADHD 三重奏家族的外显子组芯片数据，以识别易患 ADHD 的罕见功能性遗传变异。我们将检测外显子组中大约 200,000 个罕见的 SNP 突变。目标 2：全面分析已识别的稀有变异。完成基因分型测定后，我们将对外显子组芯片数据进行单位点和区域关联分析。然后，我们将通过利用生物信息学工具询问基因和通路来扩展这些初步分析，以提高检测基因的能力并更清楚地解释我们的主要结果。目标 3：与科学界共享所有数据。我们致力于确保此应用程序生成的所有数据都将存储在 dbGaP 以及 NIH 法规要求的任何其他数据库中。完成该项目后，我们希望为该领域提供稀有 DNA 变体的宝库，可以对其进行功能性生物学检测。这项工作意义重大，因为多动症是一种常见的儿童疾病，与儿童学业失败、精神共病和社会心理残疾有关。大多数病例持续到成年，此时该疾病还与职业失败、犯罪、交通事故、药物滥用和医疗保健利用率增加有关。健康经济学研究表明，成年后，多动症每年给社会造成的损失在 77.5 至 1159 亿美元之间。目前的治疗仅部分有效，并且不存在预防性治疗。需要新的治疗目标来开发更好的药物来治疗病人，或许还可以预防易感人群的疾病。