Convergent Genetic and Genomic Analyses of Schizophrenia

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遗传变异。具体目标：1。对染色体5 q上的一个连锁区域进行测序。2.使用统计学和生物信息学标准的组合对Aim 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精神分裂症相关，我们的样本是葡萄牙岛收集（PIC）。这将通过在400例病例和400例对照中对Aim 2中的1536种最有希望的变体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一再涉及染色体5 q。我们使用两组独立的遗传标记（微卫星和单核苷酸多态性[SNP]）在PIC中观察到连锁。最近发表的大样本全基因组关联研究（GWAS）（包括PIC）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的必要策略，因为标准的关联作图方法可能无法检测到它们。在上一个资助期间，我们的PIC GWAS证明了编码离子型谷氨酸受体AMPA 1亚型（GRIA 1）的基因及其周围的一组相关SNP，该基因位于5 q上。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：我们计划在24对精神分裂症同胞和24名对照中对染色体5 q连锁区的30 MB进行测序。在第一阶段，即发现阶段，我们将利用PIC的家族结构，该结构来自于群体分离株。如果受影响的兄弟姐妹共享变异体，但对照组中未出现变异体，则将优先考虑这些变异体。我们计划使用NimbleGen序列捕获阵列以最有效的方式划分5 q区域。随后将使用“下一代”Illumina Genome Analyzer II进行测序。在第二阶段或关联阶段，我们将使用Illumina GoldenGate测定法在PIC中的400例病例和400例对照中测试具有最高优先级的1536个SNP。 公共卫生相关性： 精神分裂症是一种毁灭性的神经精神疾病，在美国每年花费365亿美元，使其成为主要的公共卫生问题。全国退伍军人管理局系统估计有9万名精神分裂症或其他精神病患者。虽然在揭示精神分裂症的遗传基础方面取得了重大进展，但目前还没有已知的特定遗传变化（突变）会导致不同种族群体的疾病。大多数以前的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是很重要的，因为它们可能很罕见。需要确定基因组区域的遗传序列，以确定更可能直接导致疾病的罕见突变。这些突变的鉴定可能会为疾病的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。

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.