Multicenter Genetic Studies of Schizophrenia

描述(由申请人提供)：这是一份修订后的为期四年的竞争性延续方案，用于精神分裂症的协作链接和关联研究，在狭义诊断模式下对860个信息丰富的家系进行多中心抽样。七个站点中的四个作为协作R01(宾夕法尼亚大学、霍普金斯大学、西北大学、弗吉尼亚大学)和三个站点(威尔士大学、巴黎第六大学、澳大利亚大学)作为宾夕法尼亚大学的联合体参与。研究人员对20个精神分裂症基因组扫描进行了荟萃分析，发现了一组有重要证据表明扫描之间存在关联的区域。来自大样本的连锁和关联数据可以缩小候选区域，便于识别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。遗传病研究中心(CIDR)将键入388个标记，这样数据就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在一起，总共有2000多个家系。澳大利亚基因组研究机构将从高密度筛选图谱中再输入217个标记，当与CIDR图谱结合时，选择这些标记形成最均匀分布的6 cM图谱。更密集的图谱可以增加所提出的连锁分析和基因座间相互作用分析的能力。维度精神病理学评分也将完成整个样本，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链接精细绘图研究，以最大限度地提供链接信息，并缩小每个区域的1-LOD支持间隔。在本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连锁证据的区域进行LD图谱研究(LLUMINA)，以确定特定的位置候选基因。在一个大的多重系谱样本中进行这些研究绕过了种群分层的问题，并允许分析在一个关联区域的关联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图谱和复制研究的基因类型将与诊断和维度精神病理学评级和因素评分一起公开。 为了回应审查者的建议，这一修订后的应用包括降低基因分型成本，将大多数微卫星和SNP标记的基因分型集中在高通量实验室，以提高质量控制和效率，以及改进维度临床评级部分。

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.