Genetics of Schizophrenia in Oceanic Palau.

描述(由申请人提供)：我们的主要目标是确定帕劳海洋人口中精神分裂症和其他精神障碍(以下称为SCZ)易感性的基因变异。我们将利用调查人员与帕劳政府十多年来的持久关系所获得的广泛科学专门知识和令人难以置信的人口样本来实现这一目标。我们现在有关于数千个个体的系谱信息，这些个体构成了全基因组连接和关联图谱的令人信服的资源，并代表了从帕劳海洋种群中完全确定的。我们建议通过使用Affymetrix芯片技术对250,000个单核苷酸多态(SNPs)的500个个体进行基因分型，从而对SCZ风险的连锁和关联进行全基因组研究。我们使用这些基因类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检验一个新的假设--最初对SCZ的易感性是在胎儿发育过程中由一个或多个环境应激源产生的，但它是由母亲对应激的遗传脆弱性促进的，因此胎盘环境不能充分缓冲发育中的胎儿。为了有效地寻找在任何水平上(母体或个体)影响风险的变异，我们建议对基本上所有受SCZ影响的个体、250、150名被诊断为SCZ的个体的母亲和100名对照个体进行基因分型。另外450人的DNA将用于后续分析。将为这一人群收集一组丰富的风险母体风险因素，并将其用于我们的分析。统计分析将以识别扩展的单倍型为目标，这些单倍型的共享频率比预期的要高得多(在任何风险水平下)。这种单倍型的鉴定将通过该种群和其他海洋种群的延伸连锁不平衡特征来促进。分子和精细图谱研究将确定风险基因座。我们相信，这项研究在SCZ遗传学研究中是独一无二的，因为它的人群、样本、研究团队以及假设和方法的新颖性。

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.