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: 8445147
• 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/8445147
• 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; risk variant; 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.

描述（由申请人提供）： 项目摘要/摘要目的：确定增加精神分裂症风险的常见和罕见的遗传变异。具体目的：1。测序5q染色体上的链接区域。 2。使用统计和生物信息学标准组合在AIM 1中发现的最有希望的变体。 3。确定（1）中发现的遗传风险变异是否与精神分裂症有关，我们的样本，葡萄牙岛收集（PIC）。这将通过在AIM 2中的400例和400个对照中的AIM 2中的1536个最有希望的变体来完成。背景：精神分裂症是退伍军人健康管理局的主要健康问题。在多个独立样品中进行的精神分裂症的连锁研究反复与5q染色体有关。我们使用两组独立的遗传标记（微卫星以及单核苷酸多晶型物[SNP]）观察到PIC中的联系。最近发表的大型样本（包括PIC）的全基因组关联研究（GWAS）强烈暗示了精神分裂症发病机理中的罕见变异。重新取证将是绘制疾病变体的必要策略，因为标准的关联映射方法可能无法检测到它们。在最后一个资金期间，我们的PIC GWA在编码离子型谷氨酸受体AMPA 1同工型（GRIA1）的基因中显示了一群相关的SNP，该基因为5Q。精神分裂症的谷氨酸假说强烈支持了这一发现。提出的方法：我们计划在24个兄弟姐妹对中的5Q连杆区域的30 MB序列，精神分裂症和24个对照组。在第一个或发现阶段，我们将利用来自人群分离的PIC的基于家庭的结构。如果变体由受影响的兄弟姐妹共享，但不会在对照中进行。我们计划使用敏捷序列捕获阵列以最有效的方式对5Q区域进行分区。随后将使用“下一代” Illumina Genome Analyzer II进行测序。在第二个或关联阶段，我们将使用Illumina Goldengate测定法测试1536个SNP具有最高优先级的1536个SNP。