GENETIC LINKAGE STUDIES OF THE AFFECTIVE DISORDER

这是五个临床中心四年提案的重新提交。 对情感性精神障碍进行遗传连锁研究。我们会 对20个家系的亲属进行第三次临床评估 系统地从NIMH协作组的612个家庭中挑选出来 抑郁症研究。我们将研究至少有四个家庭的20个家庭 采访的成员患有原发性重度抑郁症，没有躁狂症或 轻躁狂症。这些家系将扩大到包括150个新的 亲戚。将抽取血液以建立淋巴母细胞系 细胞系的建立和高分子量DNA的制备。系统化 用一组高度多态的DNA作图20个家系 横跨整个人类基因组的标记将完成。两者都使用 允许异质性的似然和非参数方法 家系、DNA标记与情感障碍的遗传联系 将使用从分离分析中获得的参数来识别。 这项拟议的研究有两个独特的方面。首先，它利用一个 现有的具有良好特征的“真正繁育”家系的集合。 其次，它利用家庭成员诊断的重复措施来 修改分离和连锁分析。这提供了更多 最终诊断的精确度，并提供潜在的减少 “假阳性”，尤其是在考虑到 抑郁症。基于寡聚基因的模拟研究 传输表明我们有足够的功率通过增加 通过减少测量误差的影响而获得的遗传力。 此外，通过使用系统抽样的家庭，量化 遗传方法可用于检测家系特异的遗传和 表型异质性。连锁关系的发现将有助于描绘 情感性精神障碍的病理生理及发展历程 有可能成功地进行早期干预。 在这次重新提交中，我们删除了BP-II和混血家庭，以及 只关注20个MDD家系的样本。我们已经确定了一个 另外35个MDD家庭将作为“替代”样本。 最后，我们删除了PHDD和医疗史II表，并 扩展了我们对另一个的可靠性/效度的讨论 仪器和程序。

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.