Genetic dissection of the mood-psychosis interface.

Since Kraepelin first dichotomised the functional psychoses into dementia praecox and manic-depressive insanity at the end of the 19th century, the validity of the distinction has been challenged. Phenomenological, neurobiological, family, and molecular-genetic studies suggest that there is no neat biological distinction between these entities which are now known as schizophrenia and bipolar disorder. The aim of this thesis was to explore the familial correlation of clinical measures within a large harmonised clinical dataset comprising samples of (a) families enriched for bipolar disorder, and (b) families enriched for schizophrenia. Analyses were performed across traditional diagnostic boundaries. I carried out systematic clinical ratings on 835 individuals previously collected as part of ongoing molecular genetic studies. After an intensive training period, which included reliability exercises, I rated each case on approximately 200 variables, including a new set of rating scales developed as part of the PhD project. I performed mixed-effects regression analysis on the data to estimate the intra-class correlation coefficient (ICC) and significance for each variable. After controlling for sample-of-origin and gender, thirty-one variables were significantly correlated within families. Amongst the most significant were age at onset (ICC=0.287, p=0.0006), longest admission (ICC=0.287, p=0.0006) and cannabis abuse/dependence (ICC=0.639, p=0.0007). Such variables may be influenced by genetic factors and may therefore be used to identify subgroups of patients more likely to share common underlying genetic susceptibilities. In an analysis of a subset of sibling-pairs that were enriched for schizoaffective disorder I found that genetic similarity at chromosome lq42 was significantly associated with phenotypic similarity for the most severe depressive episode. I also undertook clinical ratings on a sample of previously-collected patients with Velo-Cardio-Facial Syndrome (VCFS) and found high-rates of both mood-disturbance and psychosis. My findings show that clinical ratings can be a useful adjunct to categorical diagnoses and identify specific phenotypes to consider in genetic studies