Quantifying the impact of rare mutations on ADHD

描述(申请人提供)：遗传学的技术革命开始产生ADHD的结果。罕见的拷贝数变异已被确定为ADHD的危险因素，为ADHD的风险提供了第一个分子证据。相比之下，到目前为止，单核苷酸多态(SNPs)的全基因组关联研究尚未明确确定易患ADHD的风险因素，最新的荟萃分析总计2,064个TRIO，896个病例和2,455个对照。这种缺乏进展的情况与ADHD遗传性、双胞胎和家人的注意力和活动水平的强有力证据形成鲜明对比 学习。在对这种脱节的几种可能解释中，有几种可能的解释是，罕见的SNP会增加ADHD的风险。鉴于罕见的CNV明显在ADHD的病理生理学中发挥作用，因此也有可能存在罕见的大效应SNPs。我们提议进行第一项研究，全面确定从基因编码区提取的罕见SNPs在疾病病因中的作用。我们将通过使用新开发的外显子组芯片来实现这一点，这是一项创新的、具有成本效益的技术，将使我们能够分析在人类基因组编码区发现的大约20万个罕见的SNPs。这种外显子芯片分析方法应该能捕获欧洲人群中等位基因频率阈值为0.1%的几乎所有SNPs，并捕获约80%的变异，等位基因频率为0.02%。我们的具体目标是：目标1：在1800个ADHD三重奏中检测罕见的变异。我们将生成总计1800个ADHD三联体家族的外显组芯片数据，以确定易患ADHD的罕见功能遗传变异。我们将检测大约200,000个罕见的外显子SNP突变。目的2：综合分析已识别的罕见变异。在完成基因分型分析后，我们将对外显子芯片数据进行单基因座和区域关联分析。然后，我们将利用生物信息学工具，通过询问基因和途径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初步结果。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和NIH法规要求的任何其他数据库中。在完成这个项目后，我们希望为这个领域提供一个稀有DNA变异的宝库，可以用功能性的生物学分析进行后续研究。这项工作意义重大，因为ADHD是一种常见的童年障碍，与儿童时期的学业失败、精神共病和心理社会残疾有关。大多数病例持续到成年，当这种疾病还与职业失败、犯罪行为、交通事故、药物滥用和医疗保健利用率增加有关时。健康经济学研究表明，成年后，ADHD每年给社会造成的损失在775亿至1159亿美元之间。目前的治疗方法只有部分有效，并且没有预防性的治疗方法。需要新的治疗目标来开发更好的药物来治疗生病的患者，或许还可以预防易感人群的这种疾病。

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.