GENETIC LINKAGE STUDIES OF THE AFFECTIVE DISORDER

这是五个临床中心四年提案的重新提交 进行情感障碍的遗传连锁研究 我们将 对20个家系的亲属进行第三次临床评估 从NIMH合作的612个家庭中系统地选择 抑郁症研究。 我们将研究20个家庭， 采访了患有原发性重性抑郁症的成员，没有躁狂症， 轻躁狂 这些谱系将扩大到包括150个新的 亲戚 将抽取血液用于建立淋巴母细胞样 细胞系和高分子量DNA的制备。 系统 用一组高度多态性DNA对20个家系进行作图 跨越整个人类基因组的标记将完成。 同时使用 可能性和非参数方法，允许异质性之间 家系，DNA标记和情感障碍之间的遗传联系 将使用分离分析获得的参数进行识别。 拟议的研究有两个独特的方面。 首先，它利用了 现有的收集良好的特点'真正的育种'谱系。 其次，它利用家庭成员诊断的重复测量， 修改分离和连锁分析。 这增加了 准确地作出最终诊断，并提供潜在的减少 “假阳性”，特别是当考虑到光谱时， 抑郁症 基于寡基因的模拟研究 传输表明，我们有足够的权力，通过增加 通过减少测量误差的影响来提高遗传力。 此外，通过使用系统抽样的家庭， 遗传学方法可用于测试谱系特异性遗传和 表型异质性 这种联系的发现将有助于描述 情感性精神障碍的病理生理和发展历程 具有成功早期干预的潜力。 在这次重新提交，我们已经删除了BP-II和混合家庭， 仅关注20个MDD家系的样本。 我们确定了一个 另外35个MDD系列将作为“替代”样本。 最后，我们放弃了PHDD和病史II表， 扩大了我们对其他人的可靠性/有效性的讨论 工具和程序。

This is a resubmission of a four year proposal from five clinical centers to conduct a genetic linkage study of the Affective Disorders. We will perform a third clinical assessment of relatives in 20 pedigrees systematically selected from 612 families of the NIMH Collaborative Depression Study. We will study 20 families with a least four interviewed members with primary major depression and none with mania or hypomania. These pedigrees will be extended to include 150 new relatives. Blood will be drawn for the establishment of lymphoblastoid cell lines and the preparation of high molecular weight DNA. Systematic mapping of the 20 pedigrees with a panel of highly polymorphic DNA markers spanning the entire human genome will be completed. Using both likelihood and non-parametric methods which allow for heterogeneity among pedigrees, genetic linkages between DNA markers and affective disorders will be identified using parameters obtained from segregation analysis. The proposed study has two unique aspects. First, it utilizes an existing collection of well characterized 'true breeding' pedigrees. Secondly, it utilizes repeated measures of family member diagnoses to modify segregation and linkage analyses. This provides increased precision in making final diagnoses and offers potential reduction of "false positives" particularly when considering the spectrum of depressive disorders. Simulation studies based on oligogenic transmission indicate we have sufficient power by increasing the heritability through reduction of the effects of measurement error. Moreover, by using families sampled in a systematic way, quantitative genetic methods may be applied to test for pedigree specific genetic and phenotypic heterogeneity. The discovery of linkage would help delineate the pathophysiology and developmental course of the affective disorders with the potential of successful early intervention. In this resubmission, we have removed the BP-II and mixed families, and focus only on the sample of 20 MDD pedigrees. We have identified an additional 35 MDD families that will serve as a "replacement" sample. Finally, we have dropped the PHDD and Medical History II Form and expanded our discussion of the reliability/validity of the other instruments and procedures.