2/2-Expanding Rapid Ascertainment Networks Of Schizophrenia Families In Taiwan

描述(由申请人提供)：本提案回应申请RFA-MH-08-131，寻求合作R01申请，建议丰富NIMH人类遗传学倡议中现有的精神分裂症资源，并应用基因组方法进一步了解精神分裂症的分子病因学。这项建议的首要目标是快速和具有成本效益地确定受精神分裂症影响的三个家庭的大样本，并在第一次基于家庭的全基因组关联研究(GWAS)中发现这种疾病的因果变异。在我们最近完成的NIMH资助的精神分裂症遗传连锁研究(R01MH059624；PI：Ming T.Tsuang)中，我们在台湾建立了一个庞大而有效的查明网络和基础设施，将在拟议的研究中再次利用和扩展。通过在这一框架内的进一步确定，我们将收集5,000个Trio的总样本，这些样本具有足够的能力在GWA中检测那些对疾病风险做出微小贡献的变异。我们将通过实现以下几个具体目标来实现这个项目的总体目标：1)通过快速筛选和收集另外3,800个来自台湾的确定地点的额外3,800个三联体，补充我们之前从台湾收集的1200个受汉族人精神分裂症影响的核心家庭样本；2)评估精神分裂症与全基因组单核苷酸多态及其组成单倍型的关联；3)对与精神分裂症有关的拷贝数变异进行全基因组调查；4)测试基因-基因相互作用(上位性)；5)测试基因-环境相互作用，如公认的出生季节影响；6)分析精神分裂症的量化表型，如症状评分和发病年龄；以及7)通过将所有临床数据、生物材料和基因型别发送到适当的存储库，加强NIMH Genetics Initiative收集。该项目将通过丰富NIMH人类遗传学倡议的现有资源和应用最新的基因组研究方法来进一步了解这种疾病的分子病因学，从而实现RFA的目标。此外，通过利用现有的临床基础设施和有效的筛查和评估方案，我们将以非常快速和具有成本效益的方式获得动力良好的样本。

DESCRIPTION (provided by applicant): This proposal responds to Request for Applications RFA-MH-08-131, which seeks Collaborative R01 applications that propose to enrich pre-existing resources for schizophrenia in the NIMH Human Genetics Initiative and to apply genomic methods to further our understanding of the molecular etiology of the disorder. The overarching aims of this proposal are to quickly and cost-effectively ascertain a large sample of trio families affected by schizophrenia, and to discover causal variants for the disorder in the first family-based genome-wide association study (GWAS) of the illness. In our recently completed NIMH-funded Genetic Linkage Study of Schizophrenia (R01MH059624; PI: Ming T. Tsuang), we established a large and efficient ascertainment network and infrastructure in Taiwan, which will again be utilized and expanded in the proposed study. Through additional ascertainment within this framework, we will collect an aggregate sample of 5,000 trios with adequate power for detecting in a GWAS those variants that make even small contributions to the risk for the disorder. We will meet the overarching goals of this project by accomplishing several Specific Aims, as follows: 1) Supplement our previously collected sample of 1,200 Han Chinese schizophrenia-affected nuclear families from Taiwan by rapidly screening and collecting an additional 3,800 trios from ten ascertainment sites in Taiwan; 2) Assess the association of schizophrenia with a genome-wide panel of single-nucleotide polymorphisms and their constituent haplotypes; 3) Perform a genome-wide survey for copy-number variations related to schizophrenia; 4) Test for gene-gene interactions (epistasis); 5) Test for gene-environment interactions, such as the well-established effect of season of birth; 6) Analyze quantitative schizophrenia phenotypes, such as symptom scores and age at onset; and 7) Enhance the NIMH Genetics Initiative collections by sending all clinical data, biomaterials, and genotypes to the appropriate repositories. The project would achieve the goals of the RFA by enriching the existing resources of the NIMH Human Genetics Initiative and by applying the latest genomic research methods to further our understanding of the molecular etiology of the disorder. Also, by capitalizing on an existing clinical infrastructure and an efficient screening and assessment protocol, we will obtain a well-powered sample in a very rapid and cost-effective manner.