Research Group 'Psychiatric Genetics', Head: Prof. Dr. Hans H. Stassen

Department of Psychiatry, Psychotherapy and Psychosomatics

Psychiatric Hospital, University of Zurich


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.


Angst J., Scharfetter C, Stassen HH: Classification of Schizoaffective Patients by Multidimensional Scaling and Cluster Analysis. Psychiatria Clin 1983; 16: 254-264
Angst J, Bänninger R, Nüsperli M, Scharfetter C, Stassen HH: Syndromale Gruppierungen endogener Psychosen in genetischer Sicht. In: Perspektiven der Schizophrenie-Forschung, ed: Pflug B., Foerster K., Straube E.; Fischer, Stuttgart New York, 1985: 25-38
Stassen HH, Scharfetter C, Angst J: Morbid risks of subgroups of affective disorders: some methodological and empirical results. J Psychiat Research 1987; 21: 347-355
Stassen HH, Scharfetter C, Winokur G, Angst J: Familial syndrome patterns in schizophrenia, schizoaffective disorder, mania and depression. Eur Arch Psychiatr Neurol Sci 1988; 237: 115-123
Angst J, Stassen HH, Gross G, Huber G, Stone MH: Suicide in affective and schizoaffective disorders. In: Marneros A. and Tsuang M.T. (eds) Affective and Schizoaffective disorders. Springer, Berlin-Heidelberg 1990: 168-185
Stassen HH, Schmid GB, Gross G, Angst J, Huber G: Prädiktoren des langfristigen Verlaufs schizophrener Erkrankungen. In: G. Huber (ed), Idiopathische Psychosen: Psychopathologie, Neurologie, Therapie. Schattauer, Stuttgart-New York, 1990: 95-104
Scharfetter C, Stassen HH: Psychopathological concepts. Psychopathology 1995; 28: 8-12
Stassen HH, Ragaz M, Reich T: Age-of-onset or age-cohort changes in the lifetime occurrence of depression? Psychiat Genetics 1997; 7: 27-34
Angst J, Stassen HH: Methodische Probleme der Prüfung von Antidepressiva. In: Stieglitz RD, Fähndrich E, Möller HJ (eds): Syndromale Diagnostik psychischer Störungen. Hogrefe, Göttingen 1998: 5-12
Angst J, Angst F, Stassen HH: Suicide risk in patients with major depressive disorder. J Clin Psychiatry 1999; 60,2: 57-62
Angst F, Stassen HH, Clayton PJ, Angst J: Mortality of patients with mood disorders: follow-up over 34 to 38 years. J Aff Disorders 2002; 68: 167-181
Stassen HH: Veränderungen der Sprechmotorik. In: T.Jahn (ed) Bewegungsstörungen bei psychischen Erkrankungen. Springer Heidelberg 2004: 107-125
Angst J, Sellaro R, Stassen HH, Gamma A: Diagnostic conversion from depression to bipolar disorders: results of a long-term prospective study of hospital admissions. J Aff Disorders 2005; 84(2-3): 149-157
Stassen HH, Angst J, Scharfetter C, Szegedi A: Therapie mit Antidepressiva: Erfolg von genetischen Faktoren abhängig? Leading Opinions, Neurologie & Psychiatrie 2005; 6: 25-27
Stassen HH, Scharfetter C: Ethnische Zugehörigkeit und Vulnerabilität am Beispiel der Affektkrankheiten und Schizophrenien. Die Psychiatrie 2005; 2: 85-95
Stassen HH, Angst J, Scharfetter C: Genetik affektiver Störungen —der quantitative Ansatz syndrom-orientierter Modelle. In: M. Leuzinger-Bohleber, S. Hau, H. Deserno (hsg): Depression –Pluralismus in Praxis und Forschung, Vandenhoeck & Ruprecht, Göttingen, 2005, pp. 219-257
Stassen HH, Scharfetter C, Angst J: Functional Psychoses —Molecular-genetic Evidence for a Continuum. In: A. Marneros and H.S. Akiskal (eds) The overlap of affective and schizophrenic spectra. Cambridge University Press 2006; pp. 55-78
Stassen HH, Scharfetter C: Vulnerability, resilience and response to psychotropic drugs: shared genetic factors? Am J Med Genetics 2006; 141: 707-708
Stassen HH, Angst J, Hell D, Scharfetter C, Szegedi A: Is there a common resilience mechanism underlying antidepressant drug response? Evidence from 2848 patients. J Clin Psychiatry 2007; 68(8): 1195-1205

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.
[ Mail to Webmaster ] k454910@bli.uzh.ch