Psychiatric University Hospital Zurich
Research Group 'Psychiatric Genetics'
Tel. +41 44 389 1586
Fax +41 44 389 1596
Distinct individuality of human brain-wave patterns, genetically determined characteristics of brain-wave patterns, non-genetic pathologic changes of brain-wave patterns throughout the course of psychiatric disorders, brain maturation and the development of brain-wave patterns; affective state and voice: speaking behavior and voice sound characteristics in depressive and schizophrenic patients; onset and time course of improvement under antidepressants and antipsychotics that differ greatly in their biochemical and pharmacological actions; genetic vulnerability to the functional psychoses “schizophrenia”, “schizoaffective disorder”, and “bipolar illness”, family studies, syndrome-oriented, quantitative approaches to psychopathology; genetic vector spaces; decomposition of genetic diversity in terms of “biological ethnicity”: the extent to which ethnic subgroups exhibit different pathways to the same manifest phenotype; the genetics of complex, non-Mendelian disorders where (1) the contributions of single loci are small, (2) the single loci are, by themselves, neither necessary nor sufficient for developing the phenotype, (3) significant interactions between the loci are involved, and (4) different pathways to the phenotype in ethnically diverse populations exist.
Psychiatric disorders, brain-waves, speech analysis, psychotropic drugs, molecular genetics, genetic vector spaces
2 research fellows, 1 scientific programmer, 2 technicians
Evidence from previous studies has suggested that the inter-individual differences in human brain-wave patterns (EEG) are predominantly determined by genetic factors. In particular, the within-pair EEG concordance of monozygotic (mz) twins was found to be typically as high as r = 0.81 across channels and frequency bands, thus being comparable to that between repeated assessments on the same individual with typically r = 0.83. Yet our investigations into mz twins discordant and concordant for schizophrenia yielded a significantly reduced within-pair EEG concordance for both, the pairs discordant for schizophrenia and the pairs concordant for schizophrenia. For the within-pair correlation of the global EEG parameter “total power 0‑32 Hz”, for example, we found a value of r = 0.772 for the healthy twins which is typical of normal mz twins, a reduced value of r = 0.513 for the twins discordant for schizophrenia, and an extremely low correlation of r = 0.210 for the twins concordant for schizophrenia. A multivariate discriminant function of EEG parameters distinguished reproducibly between affected and unaffected subjects at an overall performance of >75% correctly classified subjects, while the severity of illness, as derived from EEG-differences between affected and unaffected subjects, was closely related to the severity of illness as provided by psychopathology syndrome scores. Consequently, EEG anomalies associated with schizophrenia and manifested differently in the mz co‑twins concordant for schizophrenia are likely the effect of nongenetic, pathologic processes that evolved independently in the co‑twins’ genetically identical brains once the illness began to progress. The existence of such nongenetic processes suggests a modification of standard phenotype-to-genotype search strategies that aim to link the schizophrenia phenotype to genetic vulnerability factors.
Our investigations into the time characteristics of psychotropic drug response, encompassing 3’045 patients treated with antidepressants, neuroleptics, and placebo have demonstrated that effective psychotropic drugs merely trigger and maintain conditions necessary for recovery, with virtually identical time courses of improvement under all active compounds and placebo across genders. Differences in efficacy between active drugs, as well as between active drugs and placebo, were reflected only by the proportion of patients showing a therapeutic response. Based on these findings we carried out a molecular-genetic pilot study of (1) 105 patients suffering from Major Depressive Disorder and treated with antidepressants, and (2) 152 patients suffering from functional psychoses and treated with neuroleptics. We found an oligogenic configuration of 23 genomic loci (out of 72 candidate genes selected on the basis of some a-priori evidence from other studies) having the maximal correlation with the quantitative phenotype “onset of improvement”. Using day 14 as the boundary between “early” and “late” improvement, the genetic vector space spanned by the 23 loci enabled discrimination between “early” improvers, “late” improvers, and non-improvers at a rate of > 75% correctly classified patients. No single genomic locus was either necessary or sufficient for having the phenotype. We are currently refining the oligogenic configuration of genomic loci on the basis of 544 patients treated with 7 different types of psychotropic drugs and placebo.
In a molecular-genetic family study of different US-American ethnicities (77 families with a total of 17 unaffected and 170 affected sib pairs; 276 marker loci) we searched for ethnicity-independent oligogenic susceptibility to the functional psychoses “schizophrenia”, “schizoaffective disorder” and “bipolar illness”. Specifically, we addressed the question of the extent to which genetic risk factors and their interactions constitute multigenic inheritance across populations and might constitute universal targets for treatment by treating the Afro-American families as “training” samples, while the genetically different Non-Afro-American families served as independent “test” samples. We searched for a configuration of susceptibility loci for which the between-sib genetic similarity in a sufficiently large number of affected sib pairs deviated from the expected values in the two populations under comparison. We found 12 vulnerability loci, on chromosomes 1, 4, 5, 6, 13, 14, 18 and 20, that were reproducible across the two samples under comparison and therefore likely to constitute an ethnicity-independent vulnerability model of functional psychoses. The elevated vulnerability appeared to be nonspecific and to act in such a way that exogenous factors become more likely to trigger the onset of the illnesses [Stassen et al. 2004]. We are currently refining the vulnerability model through a combined analysis of our previous study [77 multiplex nuclear families, 430 genotyped subjects] and our new study [71 multiplex nuclear families, 468 genotyped subjects], using a test-retest design.
Speech laboratory; molecular-genetic laboratory; program package Master.EEG for the analysis of brain wave patterns; program package Master.VOX for the analysis of speech behavior and voice sound characteristics; program package Master.GEN for the multivariate analysis of genotypes and the structural decomposition of genetic diversity; normative molecular-genetic databank comprising genotypes of 1’950 polymorphisms derived from 11’500 subjects and calibrated according to Zurich standards. These standards enable cross-comparisons between labs along with pooled analyses. The samples included in the databank have been specifically selected for investigations into the genetic predisposition to complex disorders, such as schizophrenia, schizoaffective disorders, bipolar illness, depression, Alzheimer disease, alcohol dependence, hypertension, and asthma.
Swiss National Science Foundation, private funds, U.S. funds in several collaborative projects
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