LINKAGE STUDIES OF SCHIZOPHRENIA

家庭、双胞胎和收养研究一直表明，基因 精神分裂症的病因学因素具有重要意义。从很早开始 在本世纪，已经有人提出，有单一的基因 对精神分裂症有“重大影响”。分子生物学的最新进展 而在统计方法中，连锁分析现在为我们提供了 第一次，用技术来严格评估这一主张。 这是一项对大量 精神分裂症的多个家系目前正在 在爱尔兰进行了确认和抽样(MH-41953)。这项研究将利用 丰富的、高度多态的DNA标记最近已经成为 几乎可以跨越整个人类基因组，以及潜在的 候选基因。这项提议旨在利用这一独特的资源 高密度爱尔兰精神分裂症家系包括：i) 人口的种族构成相对同质，这应该 减少遗传异质性问题；二)增强 确定最佳诊断标准，并估计基因频率 以及利用所获得的数据进行连锁分析所需的外显度 来自目前以流行病学为基础的大样本家庭研究 爱尔兰西部接近完工和III)接近基因 爱尔兰与冰岛和英国的关系 其中血统已被确定，表明有显著意义 与5号染色体上的标记连锁。 整个基因组的遗传标记将被分型为高密度 精神分裂症患者家庭，首先集中在以前 研究表明，这可能与精神分裂症有关。几个 分离和连锁分析的独特统计方法 将应用于数据，以便充分利用其潜力。 任何强有力的积极发现都将通过克隆其他 来自基因组中主要基因座所在位置的标记 精神分裂症可能会撒谎，以便更准确地绘制出基因座图。

Family, twin and adoption studies have consistently shown that genetic factors are of major etiologic importance in schizophrenia. Since early in this century, it has been suggested that there are single genes of "major effect" for schizophrenia. Recent advances in molecular biology and in statistical approaches to linkage analysis now provide us, for the first time, with the techniques to rigorously evaluate this claim. This is a proposal to conduct linkage analyses on a large number of multiplex pedigrees for schizophrenia that are currently being ascertained and sampled in Ireland (MH-41953). This study will utilize the abundant, highly polymorphic DNA markers that have recently become available to span virtually the entire human genome as well as potential candidate genes. This proposal seeks to capitalize on the unique resource of high density Irish schizophrenic pedigrees that include: i) a relatively homogeneous ethnic composition of the population, which should reduce the problems of genetic heterogeneity; ii) enhanced ability to determine optimal diagnostic criteria, and estimates of gene frequency and penetrance necessary for linkage analyses by utilizing data obtained from a large sample epidemiologically based family study currently nearing completion in the West of Ireland and iii) the close genetic relationship between Ireland and both Iceland and England, the countries in which pedigrees have been ascertained that demonstrate significant linkage to markers on chromosome 5. Genetic markers throughout the genome will be typed for the high density schizophrenic families, first concentrating in areas that previous studies suggest might be of potential relevance to schizophrenia. Several distinct statistical methodologies of segregation and linkage analysis will be applied to the data in order to fully utilize their potential. Any strong positive findings will be pursued by cloning additional markers from that part of the genome where a major locus for schizophrenia might lie, in order to map the locus more precisely.