Zusammenfassung
Die hohe pathogenetische Relevanz hereditärer Faktoren bei Schizophrenien steht aufgrund der Ergebnisse epidemiologischer Untersuchungen außer Zweifel. Bei komplexem Vererbungsmodus bilden in der Regel mehrere Gene mit jeweils schwachem bis moderatem Effekt gemeinsam eine individuell durchaus unterschiedliche genetische Basis zur Vulnerabilität für Schizophrenie. Weitere organische sowie psychosoziale Faktoren spielen zusätzlich eine individuell unterschiedliche, u. U. bedeutende Rolle in der Krankheitsentstehung, so dass ätiopathogenetisch ein oligo-/polygenes multifaktorielles Modell angenommen wird. An molekulargenetischen Methoden werden Kopplungs- und Assoziationsanalysen durchgeführt. Positive Kopplungsbefunde häufen sich besonders für die Chromosomen 1q, 6p, 8p, 13q und 22q. Einzelne Mutationen, für sich genommen, tragen vermutlich in der Mehrzahl der Fälle nur wenig zur Bandbreite schizophrener Merkmalsausprägungen bei, Hauptgeneffekte konnten, von einzelnen Subtypen abgesehen, bislang nicht repliziert werden. Aus der großen Zahl möglicher Kandidatengene lieferten Untersuchungen zu DRD3, DRD2 und HTR2A zwar positive Ergebnisse, jedoch bei geringen Effektgrößen. Weniger eindeutig ist die Befundlage für Allele von Dysbindin, Neuregulin 1, DAO, COMT, PRODH, ZDHHC und DISC. Die Suche nach schizophrenierelevanten Mutationen wird durch die Möglichkeit eines heterogenen Phänotyps Schizophrenie bei einheitlichem Genotyp ebenso erschwert wie durch die Möglichkeit interindividuell homogener phänotypischer Ausprägungen bei dahinter stehender schizophrenierelevanter Heterotypie im Genom. Mit dem Konzept der an neurobiologischen Phänomenen orientierten Endophänotypen könnte ein direkterer Weg beschritten werden, der von relevanten Mutationen bis hin zum Risiko für Schizophrenien führt. Wenn neurobiologische Aspekte an die Stelle schizophrener Alienation gesetzt werden, entstehen aber Erklärungsschwierigkeiten für diese komplexen Störungsbilder. Schizophrene Erkrankungen bedürfen eines Erklärungsansatzes, der auch persönlichkeits- und entwicklungspsychologische Aspekte von allem Anfang an beinhaltet, sollen nicht Topoi schizophrenen Krankseins ausschließlich auf Loci molekulargenetischer Veränderungen eingegrenzt werden.
Abstract
The high pathogenetic relevance of genetic factors in schizophrenia is beyond doubt based on the findings of epidemiological studies. By means of a complex mode of transmission, it is likely that several genes with weak to moderate effect jointly constitute a genetic basis for a vulnerability to schizophrenia that may well vary for different individuals. Other organic and psychosocial factors also play an individually different - in some cases significant - role in terms of pathogenesis, as a result of which an oligogenic/polygenic multifactor model is assumed from the standpoint of aetiopathogenetics. Molecular genetic methods consist in linkage analyses and association analyses. Positive linkage findings accumulate particularly for the chromosomes 1q, 6p, 8p, 13q and 22q. By themselves, individual mutations contribute little to the range of schizophrenic feature characteristics, it was not possible - irrespective of some subtypes - to replicate genes of major effect. From the large number of possible candidate genes, although studies on DRD3, DRD2 and HTR2A produced positive results, the magnitudes of effect were low. The findings for alleles of dysbindin, neuregulin 1, DAO, COMT, PRODH, ZDHHC and DISC are less clear. The search for schizophrenia-relevant mutations is hampered by the possibility of a heterogeneous phenotype of schizophrenia in case of a homogeneous genotype as much as by the possibility of inter-individually homogeneous phenotypical characteristics in case of schizophrenia-relevant heterotypy in the genome. With the aid of the concept of endophenotypes, based on neurobiological phenomena, it might be possible to take a more direct approach that leads from relevant mutations to the risk of schizophrenias. However, replacing schizophrenic alienation with neurobiological aspects leads to difficulties in explaining these complex disorder profiles. Schizophrenic diseases require an explanatory approach that also incorporates personality and developmental psychological aspects from the outset, if the aim is not to restrict topoi of schizophrenic disease exclusively to loci of molecular genetic changes.
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A. Univ. Prof. DDr. Hans Fabisch
Universitätsklinik für Psychiatrie · Medizinische Universität Graz
Auenbruggerplatz 31
8036 Graz, Österreich
Email: hans.fabisch@meduni-graz.at
