Molecular-genetic Validation of Syndrome-oriented Approaches to Psychopathology

Stassen H.H., Bridler R., Hägele S., Hergersberg M., Mehmann B., Schinzel A., Weisbrod M., and Scharfetter C.

Several previous investigations have suggested that the gene for the α7-nicotinic receptor may play a role in the pathogenesis of schizophrenia and may be responsible for heavy smoking among schizophrenic patients. In a study of 129 healthy controls and 127 schizophrenic, schizoaffective and bipolar patients, we aimed (1) to confirm the potential association between schizophrenia and the α7-nicotinic receptor, (2) to test the diagnostic specificity of α7-receptor subunits with respect to psychiatric diagnoses, and (3) to investigate potential receptor differences between smokers and nonsmokers in the general population. Our analysis included the two dinucleotide polymorphisms D15S1360 and L76630 that are localized in a genomic fragment containing the a7-nicotinic receptor gene CHRNA7. Highly significant differences (p < 0.0001) between the allele distributions of patients and controls were detected for these two markers, with all three diagnostic subgroups contributing to the discrimination. An independently ascertained replication sample of 24 patients confirmed this finding.

Our results suggested a nonspecific, α7-related vulnerability to functional psychoses which depended on the severity of overall psychopathology, with no clear-cut boundary between clinical diagnoses. This vulnerability was lowest among schizophrenics, intermediate among bipolars, and highest among schizoaffectives (Tables 1, 2). For the healthy control subjects, we found no association between the α7-nicotinic receptor gene and tobacco consumption and, consequently, no evidence that the differences between patients and controls could be explained through a genetic predisposition to tobacco consumption, thus indicating that the differences between patients and controls are more than just a smoker-nonsmoker distinction.

Table 1
Table 1: Diagnosis-dependent allele distribution of markers D15S1360 and L76630 among schizophrenics, bipolars and schizoaffectives as compared to healthy controls.

Table 2
Table 2: Allele distributions of dinucleotide polymorphism D15S1360 across the populations of patients and controls, as well as the diagnostic subgroups within these populations.

Specifically, we found a highly significant correlation (p < 0.001) between genotypes and severity of overall psychopathology as reflected by the co-occurrence of SSCL-16 syndromes. Subsequent discriminant analysis using both polymorphisms yielded 62% correctly classified controls and 69% correctly classified patients. These results suggest that quantitative, syndrome-oriented measures apparently possess a biological component which enables not only a direct validation of the method of approach but also an estimation of the amount of variance explained by a given configuration of genes.



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