Molecular Genetics of Schizophrenia

描述（由申请人提供）：这是一份为期4年的精神障碍合作研究（CSMD）的延续申请。研究中心和PI包括U。芝加哥（P. Gejman，协调员），贝勒（F.阿明），路易斯安那州立大学（N. Buccola），UC Irvine（W. Byerley），华盛顿大学（C.R. Cloninger）、U.爱荷华州（R. Crowe），U.科罗拉多州（共和党）Freedman）、美国种（U.宾夕法尼亚州（D。Levinson）、美国黑曲霉U.昆士兰州（B。Mowry），以及Mt. Sinai（J. Silverman）.目前，这些网站正在收集507精神分裂症（SZ）影响的同胞对（ASP）的NIMH遗传学倡议储存库添加到以前的较小的集合，并将完成基因组扫描连锁分析。 现在建议使用相同的临床评估方法收集4，500例欧洲和非洲裔美国人血统的SZ病例（加上1，800名可用的父母）的储存库样本，以及从普通人群中选择的4，500名种族匹配的对照，并启动一组实验，以综合方式使用ASP和病例对照样本克隆一个或多个SZ易感基因。 将根据我们的基因组扫描和所有SZ扫描的荟萃分析数据选择位置候选区域。在这些区域中，将在组合的遗传学倡议SZ ASP样品（620个ASP）中对微卫星标记的2 cM图谱进行分型，并且选择至少一个候选区域用于LD作图研究。 在第3年期间，将使用Illumina Corp. BeadArray方法在ASP样本和病例对照样本的前半部分中对该区域的20 kb图谱（480个SNP，= 10 MB）进行基因分型，并将在所有非洲裔美国人病例和对照以及欧洲血统病例的子集中对选择用于最大非洲-欧洲等位基因频率差异的24个微卫星进行分型。将进行遗传分析，以评估SNP变异与疾病的关联，以及该证据与支持ASP连锁的关联，同时考虑群体亚结构和混合物。在第4年，来自阳性区域的96个SNPs将在病例和对照的第二个半样本中进行分型，以进行复制和全样本分析。最后，将在相关区域中鉴定的位置候选基因中更全面地表征遗传多样性和LD结构，并在整个病例对照样本中分型288个SNP，以测试这些基因和其他研究中鉴定的SZ候选基因。本研究的目的是确定一个或多个SZ易感基因，其随后的分子和功能研究特征将阐明SZ的病理生理学和治疗。

DESCRIPTION (provided by applicant): This is an application for a 4-year continuation of a Collaborative Study of Mental Disorders (CSMD). Sites and PIs include U. Chicago (P. Gejman, coordinator), Baylor (F.Amin), LSU (N. Buccola), UC Irvine (W. Byerley), Washington Univ. (C.R. Cloninger), U. Iowa (R. Crowe), U. Colorado (R. Freedman), U. Pennsylvania (D. Levinson), U. Queensland (B. Mowry), and Mt. Sinai (J. Silverman). Currently these sites are collecting 507 schizophrenia (SZ) affected sibling pairs (ASPs) for the NIMH Genetics Initiative repository to add to a previous smaller collection, and will complete a genome scan linkage analysis. It is now proposed to collect a repository sample of 4,500 SZ cases of European and African-American ancestry (plus 1,800 available parents) using the same clinical assessment methods, and 4,500 ethnically-matched controls selected from the general population, and to initiate a set of experiments to clone one or more SZ susceptibility genes using both the ASP and case-control samples in an integrated fashion. Positional candidate regions will be selected based on our genome scan and meta-analysis data for all SZ scans. In these regions, 2 cM maps of microsatellite markers will by typed in the combined Genetics Initiative SZ ASP sample (620 ASPs), and at least one candidate region selected for LD mapping studies. During year 3, a 20 kb map of this region (480 SNPs, = 10 MB) will be genotyped in the ASP sample and the first half of the case-control sample using the Illumina Corp. BeadArray method, and 24 microsatellites selected for maximum African-European allele frequency difference will be typed in all African-American cases and controls and a subset of European-ancestry cases. Genetic analyses will be carried out to assess association of SNP variation with disease, and association of this evidence with support for linkage in ASPs, taking population substructure and admixture into account. In year 4, 96 of these SNPs from the positive regions will be typed in the second half-sample of cases and controls for replication and whole-sample analyses. Finally, genetic diversity and LD structure will be more comprehensively characterized in positional candidate genes identified in associated regions, and 288 SNPs will be typed in the entire case-control sample to test these genes and SZ candidate genes identified in other studies. The goal of the study is to identify one or more SZ susceptibility genes whose subsequent characterization inmolecular and functional studies will elucidate the pathophysiology and treatment of SZ.