Genetische Risikofaktoren schizophrener Psychosen: Genomweite Untersuchung von Copy-Number Variations (CNVs) mit Phänotyp-Korrelation.
Zusammenfassung der Projektergebnisse
A contribution of inherited or de novo copy number variations (CNVs) in the pathogenesis of schizophrenia is well established, but they have not yet been associated with specific psychiatric phenotypes. We analyzed a sample of 400 German parent-proband trios with schizophrenic psychoses according to ICD10 criteria for occurrence of de novo and transmitted copy-number variants (CNVs). Our aim was to elucidate further the role of CNVs in the etiology of schizophrenia and relation to possible clinical phenotypes. As an additional research tool, Leonhard’s classification was used to characterize in more detail clinical homogeneous sub-phenotypes in our sample. We found 18 de novo CNVs (a rate of 4.3%) which occurred in known pathogenic loci or promising new ones. The lowest de novo rate was observed in cases with good prognosis and full remission, the cycloid psychoses (1.3% vs. 5%, p=0.012). We found five duplications at the Prader-Willi/Angelman Syndrome locus (15q11-q13): one de novo and two were transmitted, one of them from an affected and one from an unaffected parent. At 12p11 we also found several recurrent duplications of 1.2Mb. One was de novo and three were transmitted, all of them from affected parents. Out of these seven carriers, five had catatonia phenotypes. ASD candidate regions were repeatedly hit by de novo or transmitted CNVs. Pathway analyses revealed an association with synaptic pathways, glutamate transmission and ARC. Our study proposes several new risk loci and replicates the role of glutamate and ARC pathways in schizophrenia. Our data suggests a link between CNV-burden and outcome, with a more prominent role of neurodevelopmental CNV risk variants in chronic cases and less in those with a good prognosis (the cycloid psychoses).
