4/4-A Genomic Approach to Schizophrenia

4/4-A 精神分裂症的基因组方法

• 批准号: 7806640
• 负责人: DAVID L. BRAFF
• 金额: $ 3.86万
• 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 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806640
• 关键词: Address; Affect; Age; Age-Years; Arts; Benign; Candidate Disease Gene; DNA; Diagnostic; Enrollment; Event; Frequencies; Funding; Future; Genes; 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; public health relevance; relating to nervous system; structural genomics; tool

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Structural mutations are increasingly recognized to play an important role in human disease. Our goal is to use state-of-the-art genomic tools to detect these mutations anywhere in the genome, and to identify genes that are more often impacted by structural mutations in persons with schizophrenia compared to healthy controls.

描述（由申请人提供）：我们的目标是识别具有精神分裂症患者的稀有或从头基因组缺失或重复的基因，并确定这些突变的功能后果。结构性基因组变异是人类遗传变异的重要原因，并且越来越涉及人类疾病。我们已经表明，在精神分裂症患者中，影响基因的罕见缺失和重复要比对照组中的频繁。这些突变不成比例地影响与神经发育有关的基因。其他研究人员表明，与对照组相比，零星精神分裂症的个体中，从头结构突变的频率高8倍。我们建议使用基于基因的设计，以鉴定精神分裂症患者的结构突变会不成比例地改变的基因。我们预计对精神分裂症很重要的基因将在不同受影响的个体中引起不同的致病突变（AIM 1）。我们还将在零星精神分裂症患者中鉴定具有从头结构突变的基因（AIM 2）。最重要的候选基因中结构突变的后果将在实验上表征，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。这些项目共同招募了1155个概率，259个受影响的亲戚和2965个未受影响的亲戚，包括431个证券和父母三重奏。控制措施将从NIMH分布5年龄> 30岁的3000名无关的无关的人中汲取。所有病例和对照将以210万特征HD2阵列筛选在全基因组的范围内相同，可以检测到缺失和重复的较小。 NIMH控件的筛选由独立资金支持。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都应刺激未来的努力，以制定更有效的治疗和预防策略。 公共卫生相关性：越来越多的结构突变在人类疾病中起着重要作用。我们的目标是使用最先进的基因组工具来检测基因组中任何地方的这些突变，并确定与健康对照相比，精神分裂症患者中经常受到结构突变影响的基因。