Genetic Study of Common Forms of Epilepsy

常见癫痫形式的遗传学研究

• 批准号: 7735749
• 负责人: Russell J BUONO
• 金额: $ 93.38万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7735749
• 关键词: Absence Epilepsy; Address; Affect; African American; Alleles; American; Animal Model; Architecture; Area; Biochemistry; Biological; Biological Assay; Candidate Disease Gene; Caucasians; Caucasoid Race; Child; Chronic; Clinical; Collaborations; Collection; Complex; Copy Number Polymorphism; Custom; DNA mapping; Data; Data Analyses; Development; Diagnosis; Disease; Disease Progression; Employee Strikes; Epilepsy; Ethnic Origin; Ethnic group; Etiology; Family; Family Study; Frequencies; Funding; Gene Frequency; Generalized Epilepsy; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Genomics; Genotype; Goals; Haplotypes; Human; Human Genome Project; Incidence; Individual; International; Juvenile Myoclonic Epilepsy; Laboratories; Lead; Light; Linkage Disequilibrium; Literature; Maps; Nucleotides; Parents; Partial Epilepsies; Pathogenesis; Patients; Phase; Phenotype; Philadelphia; Population; Predisposition; Process; Publishing; Recruitment Activity; Recurrence; Reporting; Research; Research Design; Resources; Risk; Sampling; Scanning; Scientist; Seizures; Series; Signal Transduction; Single Nucleotide Polymorphism; Specific qualifier value; Staging; Structure; System; Temporal Lobe Epilepsy; Testing; Twin Multiple Birth; United States; Validation; Variant; Work; abstracting; base; caucasian American; cohort; density; design; disability; experience; fight against; gene interaction; genetic variant; genome wide association study; genome-wide; genome-wide linkage; genotyping technology; high risk; mortality; nervous system disorder; neurobiological mechanism; public health relevance; sex; tool; transmission process

DESCRIPTION (provided by applicant): This project is designed to identify genetic variants that confer susceptibility to common forms of epilepsy including i) forms of idiopathic generalized epilepsy (IGE) such as juvenile myoclonic epilepsy (JME), childhood absence epilepsy (CAE) and idiopathic epilepsy not otherwise specified (IGE-NOS) and ii) forms of localized epilepsy including temporal lobe epilepsy (TLE) and cryptogenic focal epilepsy (CFE). The overall strategy involves a whole genome association (WGA) study design with replication, fine-mapping and DNA re- sequencing. It is organized into four Specific Aims, each of which addresses hypotheses regarding the relationship between genetic variation and susceptibility to epilepsy. The key components of the project are i) a high-throughput genotyping platform (Illumina HumanHap 610Q BeadChip) for analysis of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs); ii) an existing cohort of well-characterized Caucasian (CA) epilepsy patients (N ~ 1560) and a large collection of matched normal control individuals (N ~ 4000) already genotyped; iii) a series of parent-child trios from this cohort (N ~ 400); iv) a smaller number of African American (AA) epilepsy patients from this cohort (N ~ 125); v) a clinical network in place to collect a replication cohort of CA epilepsy patients (N ~ 1000) as well as an additional series of AA epilepsy patients (N ~ 125) that will be combined with those already available for comparison with an AA control cohort (N ~ 3000) also previously genotyped. The project will be carried out in 4 stages. Stage 1 will involve completion of a WGA study on ~2000 epilepsy patients with identification of genetic variants that associate with epilepsy. Data analysis will evaluate SNPs, SNP haplotypes and CNVs. Stage 2 will involve use of a customized BeadChip to analyze specifically the top 1% of SNPs (6,000) that are prioritized from Stage 1 in the replication cohort of CA epilepsy patients and in the parent-child trios to confirm and extend initial findings (~30,000 SNPs will be typed for refinement of respective loci). In parallel, while the collection of the replication cohort progresses, validation and confirmation of initial stage 1 findings will be performed using Taqman based assays in the existing family trios. Stage 3 will involve study of AA epilepsy patients (N ~ 250) with emphasis on variants identified as important in Stages 1 and 2. The smaller blocks of genomic linkage disequilibrium in AA individuals will facilitate fine-mapping. Finally, in stage 4, we will re-sequence up to 3 of the most significant and biologically relevant candidate genes in a panel of epilepsy patients (N = 100) and controls (N = 100). Overall we believe that this strategy has a high likelihood of identifying genetic variation that defines susceptibility to epilepsy. In summary, this project represents collaboration between clinical and basic scientists focused on identifying the genetic variants that confer susceptibility to common forms of epilepsy. It is unique in that it involves a combination of existing resources and expertise which will have a synergistic effect to propel the work forward and lead to important new discoveries relevant to diagnosis, treatment and ultimately a cure. PUBLIC HEALTH RELEVANCE: Untreated epilepsy particularly in more severe cases has a detrimental effect with respect to disease progression, disability and increased mortality. Epilepsy affects about 1 in 100 children, including all ethnic groups and both sexes. Epilepsy is among the most common cause of disability in children and the etiology of epilepsy remains unknown but a genetic component has been implicated from twin and family studies. This project proposes to study genetic variants that influence the pathogenesis of epilepsy in two large and independent cohorts by conducting a genome-wide association study using a high density tag-SNP platform.

描述（由申请人提供）：该项目旨在确定遗传变异的疾病敏感性，包括i）特发性全身性癫痫（IGE）的形式，例如少年肌癫痫（JME），儿童期缺乏症状（CAE）和临时癫痫病的症状（II），以及II的本地化症状（II II II II I否）叶癫痫（TLE）和隐源性局灶性癫痫（CFE）。总体策略涉及整个基因组关联（WGA）研究设计，并进行了复制，精细映射和DNA重新测试。它被组织成四个特定的目标，每个目标都解决了有关遗传变异与癫痫易感性之间关系的假设。该项目的关键组成部分是i）一个高通量基因分型平台（Illumina Humanhap 610Q Beadchip），用于分析单核苷酸多态性（SNP）和拷贝数变体（CNV）； ii）现有的良好特征性高加索（CA）癫痫患者（n〜1560）和大量匹配的正常对照个体（N〜4000）的队列； iii）来自该队列的一系列亲子三重奏（n〜400）； iv）该队列的少量非裔美国人（AA）癫痫患者（n〜125）； v）一个临床网络，以收集CA癫痫患者的复制队列（N〜1000）以及另外一系列的AA癫痫患者（N〜125），该患者将与已经可与AA对照组（n〜3000）进行比较的AA癫痫患者（n〜125）。该项目将在四个阶段进行。第1阶段将涉及对〜2000例癫痫患者的WGA研究，并鉴定出与癫痫相关的遗传变异。数据分析将评估SNP，SNP单倍型和CNV。第2阶段将涉及使用定制的Beadchip来分析SNP的前1％（6,000）（6,000），这些SNP（6,000）优先在CA癫痫患者的复制队列中和亲子三重复的复制队列中优先级，以确认并扩展了初始发现（将键入约30,000个SNP，以进行各个位置的细化）。同时，虽然复制队列的收集进行了进展，但将使用现有家族三重奏中的基于Taqman的测定法进行初始阶段1的验证和确认。第3阶段将涉及对AA癫痫患者（N〜250）的研究，重点是在第1阶段和第2阶段被确定为重要的变异。最后，在第4阶段中，我们将在一组癫痫患者（n = 100）和对照组（n = 100）中重新序列最多3个最重要和与生物学相关的候选基因。总体而言，我们认为该策略很有可能确定定义癫痫敏感性的遗传变异。总而言之，该项目代表着临床和基础科学家之间的合作，致力于确定赋予对癫痫的常见形式敏感的遗传变异。它的独特之处在于它涉及现有资源和专业知识的结合，这将具有协同作用，以推动工作前进并导致与诊断，治疗及其最终治愈有关的重要新发现。公共卫生相关性：未经治疗的癫痫病，尤其是在更严重的情况下，在疾病进展，残疾和死亡率增加方面具有有害影响。癫痫会影响大约100名儿童中的1个，包括所有种族群体和两个性别。癫痫是儿童残疾最常见的原因之一，癫痫病的病因仍然未知，但遗传成分与双胞胎和家庭研究有关。该项目建议通过使用高密度TAG-SNP平台进行全基因组的关联研究来研究影响两个大型和独立队列中癫痫发病机理的遗传变异。