GENETIC LINKAGE STUDIES IN AFFECTIVE DISORDERS

本延续申请的广泛目标是检测和定位 双相情感障碍及相关情感障碍的易感基因位点。 这一目标 将达到1。分型50个扩展的高密度双极家系 多态性DNA标记（这些是20个先前确定的中等- 到大尺寸的激酶，在超过1000个细胞上建立细胞系 提供信息的成员和另外30个待收集的类似谱系）; 标记分型将侧重于基因组的系统扫描，包括 候选基因，特别强调基于PCR的技术， 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 更新和扩展连锁结果的谱系（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）。 在联系分析得出结果之前，长期目标将包括： 疾病基因的鉴定和表征;定义 临床和生物学测量的相关疾病形式; 基因与环境的相互作用;以及扩大系谱名册， 复制连锁结果，评估遗传异质性，如果 适当的，足够的减数分裂事件的克隆程序。 以色列是数据收集网站。 这有几个原因 选择：1. 多代家系的可用性， 受影响的病例，随时可以进行研究。 2. 率低 酗酒和吸毒，这些情况会让精神病医生 诊断. 3. 这是一个比较不同人群的机会， cultures. 4. 先前成功的合作和有趣的发现 这需要扩展。 5. 人类研究的成本相对较低。 以色列可能是唯一符合所有这些要求的国家。 一系列独特的谱系的可用性，加上最近的 诊断程序、分子遗传技术的进展， 连锁分析，有望解开遗传机制， 是某些严重情感疾病的基础 这反过来可能会导致 对病因学、疾病分类学、病理生理学和 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.