Convergent Genetic and Genomic Analyses of Schizophrenia

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的基因变异。具体目的：1.测序染色体5q上的连锁区。2.结合统计学和生物信息学标准，对在目标1中发现的最有希望的变异进行排名。3.为了确定(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--葡萄牙岛标本(PIC)。这将通过在400例病例和400名对照中对AIM 2中最有希望的1536个变种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反复发现染色体5q。我们使用两组独立的遗传标记(微卫星和单核苷酸多态[SNPs])观察到PIC中的连锁。最近发表的对大样本(包括PIC)的全基因组关联研究(GWAS)强烈表明，罕见的变异与精神分裂症的发病机制有关。重新测序将是绘制疾病变异图谱的必要策略，因为标准的关联图谱方法可能无法检测到它们。在上一次资助期间，我们PIC的GWAS展示了编码离子型谷氨酸受体AMPA1亚型(GRIA1)的基因及其周围的一系列相关SNPs，该基因位于5q上。这一发现得到了精神分裂症的谷氨酸假说的有力支持。建议的方法：我们计划对24对符合精神分裂症和24名对照的同胞对染色体5q连锁区的30MB进行测序。在第一个阶段，即发现阶段，我们将利用PIC的基于家庭的结构，它是从种群隔离派生出来的。如果变体由受影响的同级共享，则将优先处理它们，但不会出现在控件中。我们计划使用NimbleGen序列捕获阵列以最有效的方式分割5q区域。在第二阶段，或关联阶段，我们将使用Illumina GoldenGate分析在PIC的400例患者和400名对照中测试具有最高优先级的1536个SNP。

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.