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、慢性的、使人衰弱的可变表达疾病。人们对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中起到了一定作用。然而，其机制尚不清楚。大多数研究人员认为，精神分裂症在病因上是不同的。在过去的十年中，对20多个精神分裂症易感基因座(SSL)的基因组扫描已经确定了多个可能含有SSL的区域。随后对这些扫描的荟萃分析证实了某些基因座的贡献，并确定了其他可能含有易感基因座的新区域。这项研究的长期目标是通过识别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庭和基于人群的分析进行密集的SNP基因分型，以检测SSL。根据重复的连锁分析或确认的关联，6p21、8p21、13q32和22q11染色体上的区域已经被识别出来。将使用Illumina开发的最先进的高通量、健壮和具有成本效益的SNP珠阵技术，在一个独特的遗传同质群体(德系犹太人)中进行病例对照和连锁不平衡研究。可获得418名精神分裂症患者的DNA和临床评估(281名受试者的父母DNA可用)。将提供种族匹配的德系克肯纳齐DNA筛选对照样本，用于病例/对照分析。为了确认任何检测到的风险基因，我们将确定1)300名被诊断为精神分裂症或分裂情感障碍的德系犹太人的新临床样本，以及2)另外300名种族匹配的筛查对照。核查战略将在后续病例/对照分析中使用该复制样本中的DNA。实验室计划包括1)利用创新的基于家族和病例/对照的统计方法，以检测风险单倍型，以平均25kb的密度密集搜索四个候选区域；2)对已确定的位置候选基因进行评估和测序；3)在独立样本中分阶段跟踪和验证策略。我们将公开所有的SNP基因分型数据，并将DNA和临床数据存入NIMH遗传学研究中心的国家级资料库。

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.