GENETIC LINKAGE STUDIES OF AFFECTIVE DISORDERS

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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.