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

描述（由申请人提供）：本提案响应申请请求RFA-MH-08-131，该申请寻求合作R01申请，建议丰富NIMH人类遗传学计划中已有的精神分裂症资源，并应用基因组方法进一步了解该疾病的分子病因学。该提案的总体目标是快速和经济有效地确定受精神分裂症影响的三个家庭的大样本，并在该疾病的第一个基于家庭的全基因组关联研究（GWAS）中发现该疾病的因果变异。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高效的确定网络和基础设施，这将再次在我们的研究中得到利用和扩展。通过在此框架内的进一步确定，我们将收集5,000个具有足够能力的三人组的总样本，以检测GWAS中那些对疾病风险贡献很小的变异。我们将通过实现以下几个具体目标来实现本项目的总体目标：1)通过在台湾10个确定地点快速筛选和收集额外的3,800个三人组，补充我们先前收集的1,200个台湾汉族精神分裂症核心家庭样本；2)评估精神分裂症与全基因组单核苷酸多态性及其组成单倍型的关系；3)对与精神分裂症相关的拷贝数变异进行全基因组调查；4)基因-基因相互作用（上位性）检测；5)基因与环境相互作用的检验，如出生季节的确定效应；6)分析精神分裂症的定量表型，如症状评分和发病年龄；7)通过将所有临床数据、生物材料和基因型发送到适当的存储库，加强NIMH遗传学倡议的收集。该项目将通过丰富NIMH人类遗传学计划的现有资源和应用最新的基因组研究方法来进一步了解该疾病的分子病因，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选和评估方案，我们将以非常快速和具有成本效益的方式获得良好的样品。

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.