Multicenter Genetic Studies of Schizophrenia

精神分裂症的多中心遗传学研究

• 批准号: 6892048
• 负责人: Brien P Riley
• 金额: $ 13.5万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-05 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6892048
• 关键词: behavioral genetics; clinical research; cooperative study; data quality /integrity; family genetics; gene expression; genetic markers; genetic susceptibility; genotype; human genetic material tag; human subject; linkage mapping; meta analysis; schizophrenia

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）：这是一项修订的4年竞争性延续建议，用于在狭窄诊断模型下，在860个信息丰富的家系的多中心样本中进行精神分裂症的协作连锁和关联研究。七个研究中心中有四个作为协作R 01（宾夕法尼亚大学、霍普金斯大学、西北大学、VCU）和三个研究中心（美国大学）参加。威尔士大学巴黎六世，美国W.澳大利亚）作为宾夕法尼亚大学的财团。研究人员对20个精神分裂症基因组扫描的荟萃分析确定了一组具有显著证据的区域，这些区域与扫描之间的联系有关。来自大样本的连锁和关联数据可以缩小候选区域，并有助于鉴定易感基因及其相互作用。 将使用605个标记进行新的6 cM微卫星基因组扫描。遗传疾病研究中心（CIDR）将对388个标记进行分类，以便数据可以很容易地与其他两个正在进行的大型精神分裂症基因组扫描整合，总共超过2,000个家系。澳大利亚基因组研究机构将从高密度筛选图中再选出217个标记，与CIDR图相结合，形成间隔最均匀的6 cM图。一个更密集的地图可以增加的权力，建议的连锁分析和基因座之间的相互作用。还将完成整个样本的维度精神病理学评级，并用于遗传分析。将使用2厘米微卫星图对最佳候选区域进行连锁精细绘图研究，以最大限度地利用连锁信息，缩小每个区域的一个LOD支持区间。将选择一个或多个在该样品和我们的精神分裂症基因组扫描荟萃分析中具有连锁证据的区域用于LD作图研究（Illumina）以鉴定特定位置候选基因。在一个大的多重家系样本中进行这些研究，绕过了群体分层的问题，并允许分析是否在一个连锁区域的关联的证据也解释了连锁信号。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和维度精神病理学评级和因子评分一起公开沿着。为了响应评审员的建议，该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。