Molecular Genetics of Schizophrenia

描述(申请人提供)：这是一份精神疾病合作研究(CSMD)续展4年的申请。网站和PI包括芝加哥大学(P.Gejman，协调员)、贝勒(F.Amin)、路易斯安那州立大学(N.Buccola)、加州大学欧文分校(W.Byerley)、华盛顿大学。(C.R.Cloninger)、爱荷华州(R.Crowe)、科罗拉多州(R.Freedman)、宾夕法尼亚州(D.Levinson)、昆士兰州(B.Mowry)和芒特山。西奈(J.Silverman)。目前，这些网站正在收集507对受精神分裂症(SZ)影响的兄弟姐妹对(ASP)，供NIMH Genetics Initiative储存库添加到先前较小的收集中，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4500例欧洲和非裔美国人血统的SZ病例(加上1800名可用父母)的资料库样本，并从普通人群中选择4500名种族匹配的对照，并启动一系列实验，以综合方式使用ASP和病例对照样本来克隆一个或多个SZ易感基因。所有SZ扫描的位置候选区域将基于我们的基因组扫描和荟萃分析数据来选择。在这些地区，将在Genetics Initiative SZ ASP联合样本(620个ASP)中输入2 cM的微卫星标记图谱，并至少选择一个候选区域进行LD图谱研究。 在第三年期间，将使用Illumina Corp.的珠阵方法在ASP样本和病例对照样本的前半部分中对该区域的20kb图谱(480个SNPs，=10MB)进行基因分型，并将在所有非裔美国人病例和对照病例以及欧洲血统病例的子集中对选定的24个非洲-欧洲等位基因频率差异最大的微卫星进行分型。将进行遗传分析，以评估SNP变异与疾病的关联，以及这一证据与支持ASP连锁的关联，并考虑到种群亚结构和混合。在第4年，将在病例和对照的后半样本中对阳性地区的96个单核苷酸多态进行分型，以供复制和全样本分析。最后，将在相关区域确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对288个SNP进行分型，以检验这些基因和其他研究中确定的SZ候选基因。本研究的目的是确定一个或多个SZ易感基因，其后续的分子和功能研究将阐明SZ的病理生理和治疗。

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.