Durchbruch in der Ursachenforschung bei der Schizophrenie

Zusammenfassung

Schizophrenie ist eine genetisch stark beeinflusste Störung. Adoptionsstudien legen nahe, dass der genetische Einfluss weniger der Erkrankung selbst, sondern eher der Vulnerabilität für diese Störung gilt, die sich erst unter ungünstigen Umgebungseinflüssen zur Erkrankung entwickelt. Die genetischen Einflussfaktoren werden derzeit erfolgreich auf der Ebene von DNA-Sequenzvarianten lokalisatorisch eingegrenzt und prospektiv identifiziert. Mehrere Gene sind mittlerweile als sehr wahrscheinliche Kandidaten für Dispositionsgene identifiziert: Neuregulin-1-Gen, Dysbindin-Gen, G72/G30-Gen. Weitere „heiße” Kandidaten werden diskutiert (z.B. AKT1). Die Entdeckung von Dispositionsgenen bereichert schon derzeit nachhaltig die Erforschung der Pathophysiologie der Schizophrenie.

Summary

Schizophrenia is a genetically strongly influenced disorder. Adoption studies suggest that the genetic influence is not impacting on the illness itself but on the vulnerability for this disorder. Schizophrenia emerges from vulnerability in combination with unfavourable environmental conditions. At present, based on the analysis of DNA-sequence variants the influencing genetic factors are getting successfully narrowed down and are getting prospectively identified. Meanwhile, several genes are identified as most likely candidates for disposition genes: neuregulin-1 gene, dysbindin gene, G72/G30 gene being the most promising discoveries in this respect. Further “hot” candidates are discussed (f.i. AKT1). At present, already the identification of disposition genes is enormously enriching the research into the pathophysiology of schizophrenia.

Schlüsselwörter

Schizophrenie - Dispositionsgene - Pathophysiologie

Keywords

Schizophrenia - disposition genes - pathophysiology

• Literatur

• 1 Bray NJ, Preece A, Williams NM, Moskvina V, Buckland PR, Owen MJ, O’Donovan MC. Haplotypes at the dystrobrevin binding protein 1 (DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1 expression. Hum Mol Genet 2005; 14: 1947-1954.
• 2 Caspi A, Moffitt TE. Gene-environment interactions in psychiatry: joining forces with neuroscience. Nat Rev Neurosci 2006; 07: 583-590.
• 3 Green EK, Raybould R, Macgregor S, Gordon-Smith K, Heron J, Hyde S, Grozeva D, Hamshere M, Williams N, Owen MJ, O’Donovan MC, Jones L, Jones I, Kirov G, Craddock N. Operation of the schizophrenia susceptibility gene, neuregulin 1, across traditional diagnostic boundaries to increase risk for bipolar disorder. Arch Gen Psychiatry 2005; 62: 642-648.
• 4 Gruber O, Falkai P, Schneider-Axmann T, Schwab S, Wagner M, Maier W. Neuregulin risk haplotypes are associated with hippocampal volume variations in schizophrenic patients and in non-affected family members. Am J Psychiatry. 2006 (eingereicht)
• 5 Hahn C-G, Wang H-Y, Cho D-S, Talbot K, Gur RE, Berrettini WH, Bakshi K, Kamins J, Borgmann-Winter KE, Siegel SJ, Gallop RJ, Arnold SE. Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat Med 2006; 12: 824-828.
• 6 Law AJ, Lipska BK, Weickert CS, Hyde TM, Straub RE, Hashimoto R, Harrison PJ, Kleinman JE, Weinberger DR. Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5’ SNPs associated with the disease. Proc Natl Acad Sci USA 2006; 103: 6747-6752.
• 7 Lewis DA, Gonzalez-Burgos G. Pathophysiologically based treatment interventions in schizophrenia. Nat Med 2006; 12: 1016-1022.
• 8 Li D, Collier DA, He L. Meta-analysis shows strong positive association of the neuregulin 1 (NRG1) gene with schizophrenia. Hum Mol Genet 2006; 15: 1995-2002.
• 9 Maier W, Rietschel M, Lichtermann D, Wildenauer DB. Family and genetic studies on the relationship of schizophrenia to affective disorders. Eur Arch Psychiatry Clin Neurosci 1999; 249 (Suppl. 04) 57-61.
• 10 Maier W, Zobel A, Wagner M. Schizophrenia and bipolar disorder: differences and overlaps. Curr Opin Psychiatry 2006; 19: 165-170.
• 11 Munafo MR, Bowes L, Clark TG, Flint J. Lack of association of the COMT (Val158/108Met) gene and schizophrenia: a meta-analysis of case-control studies. Mol Psychiatry 2005; 10: 765-770.
• 12 Norton N, Williams HJ, Owen MJ. An update on the genetics of schizophrenia. Curr Opin Psychiatry 2006; 19: 158-164.
• 13 Rapp AM, Leube DT, Erb M, Grodd W, Kircher TT. Laterality in metaphor processing: Lack of evidence from functional magnetic resonance imaging for the right hemisphere theory. Brain Lang 2007; 100: 142-149.
• 14 Schulze TG, Ohlraun S, Czerski P, Schumacher J, Kassem L, Deschner M, Gross M, Tullius M, Heidmann V, Kovalenko S, Jamra RA, Becker T, Leszczynska-Rodziewicz A, Hauser J, Illig T, Klopp N, Wellek S, Cichon S, Henn FA, McMahon FJ, Maier W, Propping P, Nöthen MM, Rietschel M. Genotype-phenotype studies in bipolar disorder show associations between the DAOA/G30 locus and persecutory delusions: a first step toward a molecular genetic classification of psychiatric phenotypes. Am J Psychiatry 2005; 162: 2101-2108.
• 15 Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S, Brynjolfsson J, Gunnarsdottir S, Ivarsson O, Chou TT, Hjaltason O, Birgisdottir B, Jonsson H, Gudnadottir VG, Gudmundsdottir E, Bjornsson A, Ingvarsson B, Ingason A, Sigfusson S, Hardardottir H, Harvey RP, Lai D, Zhou M, Brunner D, Mutel V, Gonzalo A, Lemke G, Sainz J, Johannesson G, Andresson T, Gudbjartsson D, Manolescu A, Frigge ML, Gurney ME, Kong A, Gulcher JR, Petursson H, Stefansson K. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 2002; 71: 877-892.
• 16 Tienari P, Wynne LC, Sorri A, Lahti I, Laksy K, Moring J, Naarala M, Nieminen P, Wahlberg KE. Genotype-environment interaction in schizophrenia-spectrum disorder. Long-term follow-up study of Finnish adoptees. Br J Psychiatry 2004; 184: 216-222.
• 17 Tunbridge EM, Harrison PJ, Weinberger DR. Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol Psychiatry 2006; 60: 141-151.
• 18 Van Os J, Bak M, Hanssen M, Bijl RV, de Graaf R, Verdoux H. Cannabis use and psychosis: a longitudinal population-based study. Am J Epidemiol 2002; 156: 319-327.
• 19 Wong AH, Gottesman II, Petronis A. Phenotypic differences in genetically identical organisms: the epigenetic perspective. Hum Mol Genet 2005; 14 Spec No 1: R11-18.