A Genome Wide SNP Association Study: Schizophrenia

描述（由申请人提供）： 精神分裂症是世界上尚未解决的主要公共卫生问题之一。它是一种相对常见的慢性衰弱性疾病，表现多样。关于精神分裂症的病因知之甚少，但有令人信服的证据表明，遗传因素在精神分裂症的病因学中起着一定的作用。然而，其机制尚不清楚。大多数研究者认为精神分裂症在病因上是异质的。在过去的十年中，超过20个精神分裂症易感基因座（SSL）的基因组扫描已经确定了可能存在SSL的多个区域。这些扫描的后续荟萃分析证实了一些基因座的贡献，并确定了其他新的区域，可能窝藏脆弱性基因座。本研究的长期目标是通过鉴定与易感性相关的基因来阐明精神分裂症的遗传异质性。我们将在四个候选染色体区域使用基于家族和基于人群的分析进行密集SNP基因分型，以检测SSL。染色体6p 21、8 p21、13 q32和22 q11上的区域已经基于重复的连锁分析或确认的关联被鉴定。将使用Illumina开发的最先进的高通量，稳健和具有成本效益的SNP BeadArray技术在独特的遗传同质社区（德系犹太人）中进行病例对照和连锁不平衡研究。有418名精神分裂症患者的DNA和临床评估可用（其中281名患者的父母dna可用）。一个种族匹配的德系犹太人DNA筛选对照样本将可用于病例/对照分析。为了确认任何检测到的风险基因座，我们将确定1）300名患有精神分裂症或情感障碍的DSM-IV诊断的德系犹太人的新临床样本，以及2）另外300名种族匹配的筛选对照。验证策略将在后续病例/对照分析中使用来自该复制样本的DNA。实验室计划包括：1）使用创新的基于家族的和病例/对照统计方法以平均25 Kb密度密集搜索4个候选区域，以检测风险单倍型; 2）对已鉴定的位置候选基因进行评价和测序; 3）在独立样本中进行分阶段随访和验证策略。我们将公开所有SNP基因分型数据，并将DNA和临床数据存款NIMH遗传研究中心的国家知识库。

DESCRIPTION (provided by applicant): Schizophrenia is one of the world's major unsolved public health problems. It is a relatively common, chronic, debilitating disease of variable expression. Little is known about the causes of schizophrenia but there is convincing evidence that genetic factors play some role in the etiology of schizophrenia. However, the mechanism is not known. Most investigators believe schizophrenia is etiologically heterogeneous. Over 20 genome scans for schizophrenia susceptibility loci (SSL) in the last decade have identified multiple regions likely to harbor SSL. Subsequent meta-analyses of these scans confirm contributions of some loci and identify other novel regions which may harbor vulnerability loci. The long-term objective of this study is to elucidate the genetic heterogeneity of schizophrenia by identifying genes associated with susceptibility. We will conduct dense SNP genotyping using both family-based and population based analyses in four candidate chromosomal regions in order to detect SSL. Regions on chromosomes 6p21, 8p21, 13q32 and 22q 11 have been identified based on replicated linkage analyses or confirmed associations. Case-control and linkage disequilibrium studies in a unique genetically homogeneous community (Ashkenazi Jews) will be conducted using state-of-the-art high throughput, robust, and cost-efficient SNP BeadArray technology developed by Illumina. DNA and clinical assessments of 418 individuals with schizophrenia are available (parental dnas are available for 281 of the subjects). An ethnically matched screened control sample of Ashkenazi DNAs will be available for case/control analyses. In order to confirm any detected risk loci, we will ascertain 1) a new clinical sample of 300 Ashkenazi Jewish individuals who have a DSM-IV diagnosis of schizophrenia or schizoaffective disorder and 2) an additional 300 ethnically-matched screened controls. A verification strategy will use DNAs from this replication sample in follow-up case/control analyses. The laboratory plan consists of a 1) a dense search of four candidate regions at an average 25 Kb density using innovative family-based and case/control statistical methods to detect risk haplotypes; 2) evaluation and sequencing of identified positional candidate genes; 3) a staged follow-up and verification strategy in an independent sample. We will make all SNP genotyping data publicly available and deposit dnas and clinical data into the national repository at the NIMH Center for Genetic Studies.