Curtis, David; (1993) Genetic linkage studies of the functional psychoses. Doctoral thesis (M.D.), UCL (University College London).

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Abstract

Applying linkage analysis to diseases with complex inheritance presents special problems, and it is necessary to give due consideration to the implications of uncertainties in diagnosis and mode of transmission. The methodology chosen was to apply genetic linkage analysis using DNA markers to a number of moderate to large pedigrees containing multiple cases of schizophrenia or manic depression (but not both). Special databases were developed and computer programs written to facilitate the efficient and reliable management of the large amount of data generated. In addition two new techniques were developed and validated: a method for obtaining rapid approximations to the multipoint lod score based on supplied two-point lod scores, and a method for using a dummy quantitative variable to code for different degrees of affection. New and highly polymorphic markers were typed in the cohort of schizophrenia pedigrees which had originally yielded positive lod scores with chromosome 5q markers. These resulted in lod scores which were much more negative than previously. A significant exclusion was obtained over much of the region, although a positive lod score of 2.4 remained in one of the pedigrees using the DOMSS (schizophrenia spectrum) affection model. The same region was examined in two new cohorts of pedigrees, and significantly negative lod scores were obtained. Markers on the long arm of chromosome 11 in the region of the gene for the dopamine D2 receptor yielded strongly negative lod scores. Five manic depression pedigrees were studied and a segregation analysis was performed to determine an appropriate transmission model. The best-fitting model incorporated an autosomal dominant gene with incomplete penetrance predisposing to both bipolar and unipolar affective illness in these pedigrees. Linkage analysis with markers on 5q, Xq and 9q yielded negative results, though not conclusively so for F9 on Xq27.

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