Genetics of Schizophrenia in Oceanic Palau

描述（由申请人提供）：我们的主要目的是确定帕劳的海洋人口中精神分裂症和其他精神障碍（以下称为SCZ）易感性的遗传变异。我们将利用广泛的科学专门知识和调查人员与帕劳政府十多年来的持久关系所取得的令人难以置信的人口样本来实现这一目标。我们现在拥有数千个个体的系谱信息，这些个体构成了全基因组连锁和关联作图的令人信服的资源，代表了对帕劳大洋种群的完全确定。我们提出了一个全基因组的研究连锁和关联的风险，以Scz基因分型500个人的250,000单核苷酸多态性（SNP），使用Affyssin芯片技术。我们使用这些基因型来寻找符合传统假设的变异-Scz的风险直接由受影响个体携带的遗传变异决定。我们还将使用这些数据来测试一个新的假设-最初的易感性Scz是在胎儿发育过程中产生的一个或多个环境应激源，但它是由母体遗传脆弱性的压力，使胎盘环境不能充分缓冲发育中的胎儿。为了有效地搜索影响风险的变化在任何一个层面（母亲或个人），我们建议基因型基本上所有受SCZ，250，150个母亲的个人诊断为SCZ，和100个对照个体影响。来自另外450名个体的DMA将用于随访分析。将收集这一人群的一组丰富的风险孕产妇风险因素，并用于我们的分析。统计分析的目标是识别扩展的单倍型，这些单倍型的共享频率比随机预期的要高得多（在任何一种风险水平下）。这样的单倍型的鉴定将有利于扩展连锁不平衡特性的这个和其他大洋洲人口。分子和精细定位研究将确定风险位点。我们认为，本研究的人群、样本、研究团队以及假设和方法的新奇在SCZ遗传学研究中是独一无二的。

DESCRIPTION (provided by applicant): Our principal objective is to identify genetic variation that underlies liability to schizophrenia and other psychotic disorders (henceforth called Scz) in the Oceanic population of Palau. We will accomplish this goal by capitalizing on a wide range of scientific expertise and an incredible population sample obtained by enduring relationship between the investigators and the Government of Palau for more than a decade. We now have genealogical information on many thousand individuals, who form a compelling resource for genome-wide linkage and association mapping, and represents complete ascertainment from the Oceanic population of Palau. We propose a genome-wide study of linkage and association for risk to Scz by genotyping 500 individuals for 250,000 Single Nucleotide Polymorphisms (SNPs), using the Affymetrix chip technology. We use these genotypes to search for variation conforming to the conventional hypothesis - that risk to Scz is determined directly by genetic variation carried by affected individuals. We will also use these data to test a novel hypothesis - that initial liability to Scz is generated during fetal development by one or more environmental stressors, but it is facilitated by maternal genetic vulnerability to the stress, so that the placental environment cannot adequately buffer the developing fetus. To effectively search for variation affecting risk at either level (maternal or individual), we propose to genotype essentially all individuals affected by Scz, 250, 150 mothers of individuals diagnosed with Scz, and 100 control individuals. DMA from another 450 individual will be used for follow-up analyses. A rich set of risk maternal risk factors will be collected for this population and used in our analyses. Statistical analyses will target identification of extended haplotypes that are shared much more frequently than expected by chance (in either level of risk.) Identification of such haplotypes will be facilitated by extended linkage disequilibrium characteristic of this and other Oceanic populations. Molecular and fine-mapping studies will identify risk loci. We believe this study is unique among studies of Scz genetics for its population, sample, the research team and the novelty of hypotheses and approach.