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大洋洲人口中精神分裂症和其他精神疾病（以下称为Scz）的潜在遗传变异。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的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。我们现在拥有数千人的家谱信息，这些人构成了一个令人信服的全基因组联系和关联测绘资源，代表了对帕劳大洋人口的完全确定。我们建议使用Affymetrix芯片技术，通过对500个个体的25万个单核苷酸多态性（snp）进行基因分型，对Scz风险的连锁和关联进行全基因组研究。我们使用这些基因型来寻找符合传统假设的变异，即Scz的风险直接由受影响个体携带的遗传变异决定。我们还将利用这些数据来验证一个新的假设，即胎儿在发育过程中受到一种或多种环境压力因素的影响而产生对Scz的初始倾向性，但母体对压力的遗传易感性促进了这种倾向性，因此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异（母体或个体），我们建议对所有受Scz影响的个体、25,150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DMA将用于后续分析。我们将为这一人群收集一套丰富的风险孕产妇风险因素，并将其用于我们的分析。统计分析的目标将是识别比偶然（在任何风险水平上）预期更频繁地共享的扩展单倍型。这类单倍型的鉴定将通过该种群和其他海洋种群扩展的连锁不平衡特征得到促进。分子和精细定位研究将确定风险位点。我们认为这项研究在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.