GENETIC LINKAGE STUDIES IN AFFECTIVE DISORDERS

此继续应用程序的主要目标是检测和本地化 双相情感障碍及相关情感障碍的易感基因。这个目标 将通过1.对50个扩展的高密度双极家系进行分型 具有多态DNA标记(这些是先前确定的20个中等- 建立了1000多个细胞系的超大型亲本 信息丰富的成员和另外30个待收集的类似家系)； 标记分型将侧重于对基因组的系统扫描，包括 候选基因，特别强调基于PCR的技术和 微卫星多态；2.使用范围进行连锁分析 表型和遗传模型；3.评估诊断的影响 关于连锁结果的系谱更新和扩展(这将是 通过对已经确定的家系进行后续研究来完成 综合临床评级和操作诊断标准)。 在链接分析结果出来之前，长期目标将包括： 疾病基因的鉴定和特征(S).定义 临床和生物措施中的关联疾病形式.说明 基因-环境相互作用；以及将谱系名册扩大到 复制连锁结果，评估遗传异质性，生成，如果 适当、充足的减数分裂事件，可用于克隆程序。 以色列是数据收集地。造成这种情况的原因有几个 选择：1.多代多代家系的可用性 易于研究的受影响病例。2.低利率 酗酒和吸毒，使精神病患者感到困惑 诊断。3.一次比较不同人群和 文化。4.之前的成功合作和耐人寻味的发现 需要延期的。5.人类研究的成本相对较低。 以色列可能是独一无二的，它满足了所有这些要求。 一系列独特的系谱的可获得性，加上最近 诊断程序、分子遗传学技术和 连锁分析，有望解开 某些形式的重大情感疾病是其基础。反过来，这可能会 对病因学、病因学、病理生理学和 有可能预防和治疗这些疾病。

The broad objective of this continuation application to detect and localize susceptibility loci in bipolar and related affective disorders. This goal will be attained by 1. typing 50 extended high-density bipolar pedigrees with polymorphic DNA markers (these are 20 previously ascertained medium- to-large sized kindreds with established cell lines on over 1000 informative members and an additional 30 like pedigrees to be collected); marker typing will focus on systematic scan of the genome, including candidate genes, with special emphasis on PCR based technology and microsatellite polymorphisms; 2. performing linkage analysis using a range of phenotypic and genetic models; 3. assessing the impact of diagnostic update and extension of pedigrees on the linkage results (this will be accomplished by a follow-up study of the pedigrees already identified using comprehensive clinical ratings and operational diagnostic criteria). Pending the results of the linkage analyses, long-range goals will include: Identification and characterization of the disease gene(s); definition of linked disease forms on clinical and biological measures; elucidation of gene-environment interaction; and expansion of the pedigree roster to replicate linkage results, assess genetic heterogeneity, an generate, if appropriate, sufficient meiotic events for the cloning procedures. Israel is the data collection site. There are several reasons for this choice: 1. Availability of multigenerational pedigrees with multiple affected cases that are readily accessible for study. 2. Low rates of alcoholism and drug use, conditions that confound the psychiatric diagnosis. 3. An opportunity co compare different populations and cultures. 4. Previous successful collaboration and intriguing findings that require extension. 5. The relatively low cost of human research. israel, probably uniquely, meets all these requirements. The availability of a unique series of pedigrees, coupled with recent advances in diagnostic procedures, molecular genetic techniques, and linkage analysis, holds promise for unraveling the genetic mechanisms that underlie some forms of major affective illness. This, in turn, may have important implications for the etiology, nosology, pathophysiology and, possibly prevention and treatment of these disorders.