4/4-A Genomic Approach to Schizophrenia

4/4-A 精神分裂症的基因组方法

• 批准号: 8238404
• 负责人: DAVID L. BRAFF
• 金额: $ 6.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-16 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8238404
• 关键词: Address; Affect; Age; Age-Years; Benign; Candidate Disease Gene; DNA; Diagnostic; Enrollment; Event; Frequencies; Funding; Future; Genes; Genetic Variation; Genome; Genomics; Genotype; Goals; Human; Human Genetics; Individual; Inherited; Left; Leukocytes; Mutation; Mutation Analysis; National Institute of Mental Health; Nonsense-Mediated Decay; Parents; Patients; Persons; Play; Prevention strategy; Proteins; RNA; Relative (related person); Research Personnel; Resolution; Risk; Role; Sampling; Schizophrenia; Screening procedure; Siblings; Technology; Transcript; Variant; base; case control; chimeric gene; design; disease-causing mutation; effective therapy; gene function; genome wide association study; genome-wide; genome-wide analysis; human disease; lymphoblast; neurodevelopment; neuropsychiatry; novel; proband; relating to nervous system; structural genomics; tool; treatment strategy

Our goal is to identify genes that are enriched for rare or de novo genomic deletions or duplications in persons with schizophrenia and to determine the functional consequences of these mutations. Structural genomic variants are important causes of human genetic variation and are increasingly implicated in human disease. We have shown that rare deletions and duplications that impact genes are significantly more frequent among individuals with schizophrenia than among controls. These mutations disproportionately affect genes involved with neural development. Other investigators have shown that de novo structural mutations are 8-fold more frequent among individuals with sporadic schizophrenia compared to controls. Using a gene-based design, we propose to identify genes that are disproportionately altered by structural mutations in persons with schizophrenia. We anticipate that a gene important to schizophrenia will harbor different disease-causing mutations in different affected individuals (Aim 1). We also will identify genes with de novo structural mutations in patients with sporadic schizophrenia (Aim 2). The consequences of structural mutations in the most significant candidate genes will be characterized experimentally to determine the impacts of mutations on gene function (Aim 3). Cases have been assessed and sampled by four NIMH projects. These projects together have enrolled 1155 probands, 259 affected relatives, and 2965 unaffected relatives, including 431 proband-parent trios. Controls will be drawn from >3000 unrelated unaffected persons age >30 years from NIMH distribution 5. All cases and controls will be screened identically genome-wide with NimbleGen 2.1-million feature HD2 arrays, which can detect deletions and duplications as small as 3kb. Screening of the NIMH controls is supported by independent funds. If successful, our approach will identify multiple genes important for schizophrenia. Each of these genes should stimulate future efforts to develop more effective treatment and prevention strategies.

我们的目标是确定在人中富含稀有或从头基因组缺失或重复的基因 精神分裂症并确定这些突变的功能后果。结构基因组 变异是人类遗传变异的重要原因，越来越多地与人类疾病有关。 我们已经表明，影响基因的罕见缺失和重复在 具有精神分裂症的人而不是对照组。这些突变不成比例地影响涉及的基因 随着神经发展。其他研究人员表明，从头结构突变多8倍 与对照组相比，零星精神分裂症的个体中经常发生。 使用基于基因的设计，我们建议识别通过结构不成比例改变的基因 精神分裂症患者的突变。我们预计对精神分裂症很重要的基因将具有 不同受影响个体的不同引起疾病的突变（AIM 1）。我们还将确定具有DE的基因 零星精神分裂症患者的NOVO结构突变（AIM 2）。结构的后果 最重要的候选基因中的突变将在实验中进行表征，以确定 突变对基因功能的影响（AIM 3）。 案件已由四个NIMH项目评估和采样。这些项目一起注册了1155 概率，259名受影响的亲戚和2965个未受影响的亲戚，包括431个概率和父母三重奏。控件 将从NIMH分布5年龄的30岁> 30岁的无关的无关人员中提取。所有案件和 对控件将以210万特征HD2阵列对全基因组进行筛查，可以 检测缺失和复制小至3KB。 NIMH控件的筛选由独立支持 资金。 如果成功，我们的方法将确定多个对精神分裂症重要的基因。这些基因中的每一个 应该刺激未来的努力，以制定更有效的治疗和预防策略。