GENETIC STUDY OF SCHIZOPHRENIA IN AN ETHNIC MINORITY

描述(改编自申请人的摘要)：用途广泛 承认遗传传播在疾病的主要病因学上的重要性 精神分裂症的发病机制。因此，出现了一场重大的 利用多个家系分离对连锁研究的投资 精神分裂症，是阐明精神分裂症的最佳方法之一 复杂疾病的遗传学。不幸的是，精神分裂症 孟德尔传播模式，诊断不确定，减少 外显性，表型，和可能的遗传异质性，已经证明 是一种非常难研究的疾病，有标准的连锁 技巧。 拟议的项目旨在寻找潜在的主要基因。 使用四种策略解决精神分裂症的问题 精神分裂症的遗传连锁研究中所固有的。1)表示敬意 对于家庭/受试者，调查人员建议进行例外研究 密克罗尼西亚帕劳的大型多层氏族，那里的人口 在地理和种族上与外界的遗传影响隔绝， 然而，它们不是近亲繁殖的。鉴于在这些家庭中发现了大量的兄弟姐妹关系， 愿意参与的家庭成员越多， 此地理区域内各家系间遗传同质性的概率 分离，检测与这三个家族的连锁的能力是 相当于检测200个中小型连锁店的能力 家人。调查人员还计划查明所有 精神分裂症将用于未来的连锁不平衡研究 在当前项目中发现了潜在联系的领域。2)表示敬意 对于表型鉴定，研究人员将对最大的家系进行表型鉴定 使用标准的诊断表型以及两个最 精神分裂症、SPEM和P50感觉门控有希望的内表型， 它们提供了更高的透视率和更清晰的定义 遗传模式。3)为了对这些家系进行基因分型， 调查人员将使用双管齐下的方法，包括多态 候选基因或区域和基因组扫描。4)数据将是 根据以下每项研究的具体计划进行分析。为 研究1：使用精神分裂症表型的连锁分析 来检验一个主基因的效应对 精神分裂症。对于研究2，使用心理生理学进行连锁分析 将使用内表型。调查人员将使用疾病状态 和两个内表型形成复合数量表型 这代表着精神分裂症的责任。然后他们将跟随- 总结研究1中发现的所有积极结果，使用这一更敏感的 数量连锁分析中的表型。

DESCRIPTION (Adapted from the Applicant's Abstract): It is widely accepted that genetic transmission is of major etiological importance in the pathogenesis of schizophrenia. Consequently, there has been a major investment in linkage studies using multiplex families segregating schizophrenia, one of the best available methods for elucidating the genetics of complex disease. Unfortunately, schizophrenia, with its non- Mendelian transmission patterns, diagnostic uncertainly, reduced penetrance, phenocopies, and possible genetic heterogeneity, has proven to be a remarkably difficult disease to study with standard linkage techniques. The proposed project aims to search for major genes underlying schizophrenia using four strategies that can address the problems inherent in genetic linkage studies of schizophrenia. 1) With respect to families/subjects, the investigators propose to study exceptionally large multiplex clans in Palau, Micronesia where the population has been geographically and ethnically isolated from outside genetic influences, yet is not inbred. Given the large sibships found in these families, the large number of family members willing to participate, and the greater probability of genetic homogeneity across families in this geographic isolate, the power to detect linkage with these three families is equivalent to the power to detect linkage with 200 small-to medium-sized families. The investigators also plan to ascertain all cases of schizophrenia to be used for future linkage disequilibrium studies in areas of potential linkage found in the current project. 2) With respect to phenotyping, the investigators will phenotype the largest pedigrees using the standard diagnostic phenotype as well as two of the most promising endophenotypes for schizophrenia, SPEM and P50 sensory gating, which offer the advantages of higher penetrances and more clearly defined patterns of inheritance. 3) For genotyping these pedigrees, the investigators will be using a two-pronged approach, including polymorphic candidate genes or regions and a genome scan. 4) The data will be analyzed according to the following specific plans for each study. For Study 1, linkage analysis using the schizophrenia phenotype will be used to test the hypothesis that effects of a major gene contribute to schizophrenia. For Study 2, linkage analysis using psychophysiological endophenotypes will be used. The investigators will use disease status and the two endophenotypes to develop a composite quantitative phenotype which will represent liability for schizophrenia. They will then follow- up all positive results found in Study 1 using this more sensitive phenotype in quantitative linkage analysis.