Multicenter Genetic Studies of Schizophrenia

精神分裂症的多中心遗传学研究

基本信息

批准号：
7225984
负责人：
Pablo V. Gejman
金额：
$ 6.49万
依托单位：
NORTHSHORE UNIVERSITY HEALTHSYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-05-14 至 2008-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7225984
关键词：
14p Alleles Australia Bypass Candidate Disease Gene Chromosomes Clinical Communities DNA Resequencing Data Data Set Databases Diagnosis Diagnostic Disease Disease Marker Equation Family Genes Genetic Genome Genome Scan Genotype Haplotypes Inherited Link Linkage Disequilibrium Linkage Disequilibrium Mapping Logistic Regressions Logistics Maps Meiosis Meta-Analysis Methods Microsatellite Repeats Modeling National Institute of Mental Health Numbers Paris, France Pennsylvania Phenotype Population Psychopathology Quality Control Rate Regression Analysis Reporting Research Research Personnel Sampling Scanning Schizophrenia Score Screening procedure Signal Transduction Site Stratification Structure Suggestion Susceptibility Gene Symptoms System Universities Update Wales base clinical research site cost density genetic analysis genetic association genetic linkage analysis genetic pedigree improved repository research facility response

项目摘要

DESCRIPTION (provided by applicant): This is a revised four-year competing continuation proposal for collaborative linkage and association studies of schizophrenia in a multicenter sample of 860 informative pedigrees under a narrow diagnostic model. Four of seven sites are participating as Collaborative R01s (Penn, Hopkins, Northwestern, VCU), and three sites (U. Wales, U. Paris VI, U. W. Australia) as consortia to the University of Pennsylvania. The investigators' meta-analysis of 20 schizophrenia genome scans identified a set of regions with significant evidence for linkage across scans. Linkage and association data from large samples can narrow the candidate regions and facilitate the identification of susceptibility genes and their interactions. A new 6 cM microsatellite genome scan will be carried out using 605 markers. The Center for Inherited Disease Research (CIDR) will type 388 markers so that data can be readily integrated with two other large ongoing schizophrenia genome scans for a total of over 2,000 pedigrees. The Australian Genome Research Facility will type an additional 217 markers from high-density screening maps, selected to form the most evenly-spaced 6 cM map when combined with the CIDR map. A denser map can increase the power of the proposed analyses of linkage and of interactions between loci. Dimensional psychopathology ratings will also be completed for the entire sample and utilized in genetic analyses. Linkage fine-mapping studies of the best candidate regions will be undertaken using 2 cM microsatellite maps to maximize linkage information and to narrow the one-lod support interval in each region. One or more regions with evidence for linkage in this sample and in our schizophrenia genome scan meta-analysis will be selected for LD mapping studies (lllumina) to identify specific positional candidate genes. Carrying out these studies in a large multiplex pedigree sample bypasses the problem of population stratification and permits analyses of whether the evidence for association in a linked region also explains the linkage signal. Candidate gene replication studies will also be carried out to assess emerging findings in the field. Genotypes from the genome scan, LD mapping and replication studies will be made publicly available along with diagnoses and dimensional psychopathology ratings and factor scores. In response to reviewers' suggestions, this revised application includes a reduction in genotyping costs, centralization of most of the genotyping of microsatellite and SNP markers in high-throughput labs to improve quality control and efficiency, and improvement of the dimensional clinical rating component.

描述（由申请人提供）：这是一项修订后的四年期竞争性延续提案，旨在在狭窄的诊断模型下，在 860 个信息丰富的谱系的多中心样本中进行精神分裂症的协作联系和关联研究。七个站点中的四个作为协作 R01 参与（宾夕法尼亚大学、霍普金斯大学、西北大学、弗吉尼亚联邦大学），三个站点（威尔士大学、巴黎第六大学、澳大利亚华盛顿大学）作为宾夕法尼亚大学联盟参与。研究人员对 20 个精神分裂症基因组扫描进行荟萃分析，确定了一组区域，这些区域具有跨扫描关联的重要证据。来自大样本的连锁和关联数据可以缩小候选区域的范围，并有助于识别易感基因及其相互作用。新的 6 cM 微卫星基因组扫描将使用 605 个标记进行。遗传疾病研究中心 (CIDR) 将输入 388 个标记，以便数据可以轻松地与另外两项正在进行的大型精神分裂症基因组扫描整合，扫描的样本总数超过 2,000 个家系。澳大利亚基因组研究机构将从高密度筛选图谱中额外键入 217 个标记，这些标记与 CIDR 图谱结合后将形成间隔最均匀的 6 cM 图谱。更密集的图谱可以增加对基因座之间的连锁和相互作用进行分析的能力。整个样本的维度精神病理学评级也将完成，并用于遗传分析。将使用 2 cM 微卫星图对最佳候选区域进行连锁精细绘图研究，以最大化连锁信息并缩小每个区域的单对多支持区间。在该样本和我们的精神分裂症基因组扫描荟萃分析中，将选择一个或多个具有关联证据的区域进行 LD 作图研究 (lllumina)，以识别特定位置的候选基因。在大型多重谱系样本中进行这些研究绕过了群体分层的问题，并允许分析关联区域中关联的证据是否也解释了关联信号。还将进行候选基因复制研究，以评估该领域的新发现。来自基因组扫描、LD 作图和复制研究的基因型将与诊断、维度精神病理学评级和因素评分一起公开。为了响应审稿人的建议，此修订后的申请包括降低基因分型成本、将大部分微卫星和 SNP 标记的基因分型集中在高通量实验室中以提高质量控制和效率，以及改进维度临床评级组件。