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Syndrome-Oriented Approaches to Resolving Phenotypic Heterogeneity

Zurich Family Study of Functional Psychoses

In a prospective family study ascertained through 269 index cases suffering from functional psychoses, 1501 first- and second-degree family members, and a 20-year follow-up along with the assessment of 105 offspring of the index cases, we applied a multivariate syndrome-oriented approach to psychopathology in order to derive a quantitative measure of the severity of illness and to partition the population into "natural" subgroups. Our main interest was focused on: (1) the question of increasing severity of psychoses across generations (anticipation), (2) the question of differences in the severity of psychoses depending on whether the illness has been transmitted by the maternal or paternal side (genomic imprinting), and (3) the question of age-of-onset shifts toward earlier onset of psychoses in successive birth cohorts (secular trends). Structural analyses revealed clearly distinguishable subgroups of patients, characterized by differences in the familial aggregation of syndromes and long-term outcome.

Familial Syndrome Patterns

Specifically, we carried out a multivariate cluster analysis based on the 16-dimensional, quantitative syndrome vectors derived from the 269 index cases with a diagnosis of functional psychosis, on the one hand, and from the 350 first-degree relatives who exhibited psychopathologic features in our quantitative SSCL-16 syndrome scores, on the other. We searched for "natural" groupings that equally showed up among the index cases and the affected first-degree relatives. The analysis revealed three "core" clusters which were similarly present in the two populations under investigation. These three clusters encompassed patients across diagnostic entities —that is, patients with a diagnosis of schizophrenia, schizoaffective disorder or bipolar illness. The striking similarity of quantitative syndrome patterns between index cases (n = 136) and affected first-degree relatives (n = 116), as revealed by the largest "core" cluster, is demonstrated in Figure 1.

Familial Aggregation Rather than Genetic Segregation

There are considerable inter-individual differences in the quantitative syndrome patterns within the population of index cases and the population of "affected" first-degree relatives. Specifically, within-family comparisons of syndrome patterns demonstrate that the familial aggregation of psychopathology syndromes does not follow a homotypic pattern, that is, the data of nuclear families ascertained through index cases with a clinical diagnosis of functional psychosis do not provide evidence for genetic segregation.


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Fig. 1: Striking similarity between mean quantitative syndrome patterns derived by averaging across index cases (n=136; green bars) and mean quantitative syndrome patterns derived by averaging across "affected" first-degree relatives (n=116; red bars), as revealed through multivariate cluster analysis of SSCL16 syndrome scores.
Please note: (1) there are considerable inter-individual differences in the quantitative syndrome patterns within the population of index cases and the population of "affected" first-degree relatives; (2) within-family comparisons of syndrome patterns demonstrate that the familial aggregation of psychopathology syndromes does not occur in a homotypic way, i.e., family data do not provide evidence for genetic segregation.
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