Convergent Genetic and Genomic Analyses of Schizophrenia

精神分裂症的融合遗传和基因组分析

• 批准号: 8261840
• 负责人: AYMAN H FANOUS
• 金额: --
• 依托单位: U.S. DEPT/VETS AFFAIRS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8261840
• 关键词: Affect; Algorithms; Alleles; Binding Sites; Bioinformatics; Biological Assay; Chromosomes; Classification; Collaborations; Collection; Complex; Copy Number Polymorphism; DNA Resequencing; Diagnosis; Disease; Ethnic group; European; Family; Funding; Gene Expression; Genes; Genetic; Genetic Markers; Genetic Risk; Genetic Variation; Genome; Genomics; Genotype; Glutamate Receptor; Glutamates; Health; Individual; Island; Large-Scale Sequencing; Link; Maps; Methods; MicroRNAs; Microsatellite Repeats; Molecular; Mutation; Nucleotides; Pathogenesis; Patients; Phase; Population; Promoter Regions; Protein Isoforms; Public Health; Publishing; Research Personnel; Risk; Sampling; Schizophrenia; Siblings; Structure; System; Testing; United States; Variant; Veterans; abstracting; base; chromosome 5q loss; cost; density; experience; follow-up; genetic variant; genome wide association study; health administration; neuropsychiatry; next generation; public health relevance; transcription factor

DESCRIPTION (provided by applicant): Project Summary/Abstract Objective: To identify common and rare genetic variants which increase the risk of schizophrenia. Specific Aims: 1. To sequence a linked region on chromosome 5q. 2. To rank the most promising variants discovered in Aim 1 using a combination of statistical and bioinformatics criteria. 3. To determine whether genetic risk variants discovered in (1) are associated with schizophrenia our sample, the Portuguese Island Collection (PIC). This will be done by genotyping the 1536 most promising variants in Aim 2 in 400 cases and 400 controls. Background: Schizophrenia is a major health concern in the Veterans Health Administration. Linkage studies of schizophrenia performed in multiple independent samples have repeatedly implicated chromosome 5q. We observed linkage in the PIC using two independent sets of genetic markers (microsatellites as well as Single Nucleotide Polymorphsims [SNPs]). Very recently published genome-wide association studies (GWAS) of large samples (which have included the PIC), strongly implicate rare variants in the pathogenesis of schizophrenia. Resequencing will be a necessary strategy in mapping disease variants, as standard methods of association mapping may not be able to detect them. In the last funding period, our GWAS of the PIC demonstrated a cluster of associated SNPs in and around the gene encoding the ionotropic glutamate receptor, AMPA 1 isoform (GRIA1), which is on 5q. This finding is strongly supported by the Glutamate Hypothesis of schizophrenia. Proposed Methods: We plan to sequence 30 MB of the chromosome 5q linkage region in 24 sibling pairs concordant for schizophrenia and 24 controls. In the first, or discover phase, we will exploit the family-based structure of the PIC, which is derived from a population isolate. Variants will be prioritized if they are shared by affected siblings, but do not occur in controls. We plan to use NimbleGen Sequence Capture arrays to partition the 5q region in the most efficient manner possible. This will be followed by sequencing using the "next generation" Illumina Genome Analyzer II. In the second, or association phase, we will test the 1536 SNPs having highest priority, in 400 cases and 400 controls in the PIC using the Illumina GoldenGate assay. PUBLIC HEALTH RELEVANCE: Project Narrative Schizophrenia is a devastating neuropsychiatric condition with an annual cost of $36.5 billion in the United States, making it a major public health concern. There are an estimated 90,000 patients with schizophrenia or other psychotic illnesses in the VA system nationwide. Although significant progress has been made in uncovering the genetic basis of schizophrenia, there are currently no specific genetic changes (mutations) known to cause illness across various ethnic groups. Most previous studies have only been able to identify relatively common mutations. Therefore, it will be important to use other ways of searching for mutations, as they may be rare. Determining the genetic sequence of regions of the genome is needed in order to identify rarer mutations, which are more likely to directly cause disease. The identification of such mutations may provide vital clues as to the causes of the illness as well as new treatments. In this project, we seek to determine the genetic sequence of individuals with schizophrenia and search for both common and rare mutations.

描述（由申请人提供）： 项目摘要/摘要目的：识别增加精神分裂症风险的常见和罕见遗传变异。具体目标： 1. 对染色体 5q 上的连锁区域进行测序。 2. 结合统计和生物信息学标准，对目标 1 中发现的最有希望的变体进行排名。 3. 为了确定 (1) 中发现的遗传风险变异是否与我们的样本葡萄牙岛样本库 (PIC) 中的精神分裂症相关。这将通过在 400 个病例和 400 个对照中对 Aim 2 中的 1536 个最有希望的变异进行基因分型来完成。背景：精神分裂症是退伍军人健康管理局的一个主要健康问题。在多个独立样本中进行的精神分裂症连锁研究多次表明染色体 5q 存在关联。我们使用两组独立的遗传标记（微卫星以及单核苷酸多态性 [SNP]）观察 PIC 中的连锁。最近发表的大样本（包括 PIC）全基因组关联研究 (GWAS) 强烈暗示精神分裂症发病机制中的罕见变异。重测序将是绘制疾病变异图谱的必要策略，因为关联图谱的标准方法可能无法检测到它们。在上一个资助期间，我们的 PIC 的 GWAS 展示了编码离子型谷氨酸受体 AMPA 1 同工型 (GRIA1)（位于 5q）的基因内部及其周围的一组相关 SNP。这一发现得到了精神分裂症谷氨酸假说的有力支持。建议的方法：我们计划对 24 对精神分裂症和 24 个对照的兄弟姐妹中 30 MB 的染色体 5q 连锁区域进行测序。在第一个阶段，即发现阶段，我们将利用 PIC 的基于家族的结构，该结构源自群体隔离。如果受影响的兄弟姐妹共享变异，但在对照中不出现，则将优先考虑变异。我们计划使用 NimbleGen Sequence Capture 阵列以尽可能最有效的方式划分 5q 区域。随后将使用“下一代”Illumina 基因组分析仪 II 进行测序。在第二阶段或关联阶段，我们将使用 Illumina GoldenGate 检测在 PIC 中的 400 个病例和 400 个对照中测试具有最高优先级的 1536 个 SNP。 公共卫生相关性： Project Narrative 精神分裂症是一种毁灭性的神经精神疾病，在美国每年造成 365 亿美元的损失，使其成为主要的公共卫生问题。全国 VA 系统中估计有 90,000 名精神分裂症或其他精神病患者。尽管在揭示精神分裂症的遗传基础方面已经取得了重大进展，但目前还没有已知的导致不同种族群体患病的特定基因变化（突变）。之前的大多数研究只能识别相对常见的突变。因此，使用其他方法寻找突变非常重要，因为它们可能很少见。需要确定基因组区域的遗传序列，以便识别更罕见的突变，这些突变更有可能直接导致疾病。此类突变的识别可能为了解疾病原因以及新的治疗方法提供重要线索。在这个项目中，我们试图确定精神分裂症患者的基因序列，并寻找常见和罕见的突变。