Phänotypbasierte genetische Assoziationsstudien (PGAS): Ein neuer Ansatz zum Verständnis des Genotyp-Beitrags zu schizophrenen Phänotypen

Zusammenfassung

Schizophrenien werden rein klinisch diagnostiziert. Die biologische Basis dieses Krankheitsbilds ist noch immer völlig unklar. Genetische Studien haben interessante Hinweise erbracht, jedoch nicht zur Identifizierung von Krankheitsgenotypen im eigentlichen Sinne geführt. Im Gegenteil: Es wird immer wahrscheinlicher, dass die unterschiedlichsten genotypischen Konstellationen im Zusammenwirken mit mannigfaltigen Umweltfaktoren Schizophrenien auslösen können, getreu dem Motto: „Viele Wege führen nach Rom…“ Daher sind neue Strategien erforderlich, die bessere Einblicke in die komplexen Genotyp-Phänotyp Zusammenhänge erlauben, beispielsweise PGAS (phänotypbasierte genetische Assoziationsstudien). PGAS wurde erst möglich auf der Grundlage der Göttinger Research Association for Schizophrenia (GRAS)-Datenkollektion, der bislang weltweit umfangreichsten phänotypischen Datenbank schizophrener Patienten. Erste PGAS Proof-of-Concept Ergebnisse zu kognitions- und entwicklungsrelevanten Genen liegen bereits vor.

Abstract

Schizophrenias are diagnosed purely clinically. The biological basis for this clinical entity is still fully unknown. Genetic studies have revealed some interesting hints but have not led to the identification of actual disease genotypes. On the contrary, it has become more and more probable that widely differing genotype constellations together with manifold environmental factors can trigger schizophrenia according to the motto “many roads lead to Rome...”. Thus, new strategies that allow a better insight into complex genotype-phenotype relationships, e. g. PGAS (phenotype-based genetic associations studies) are urgently needed. PGAS became possible on the basis of the GRAS data collection, the as yet largest worldwide phenotypical databank of schizophrenic patients. First PGAS proof-of-concept results on cognition or development-relevant genes are already available.

Schlüsselwörter

Schizophrenie - Phänotyp - Genotyp - genetische Assoziationsstudie

Key words

schizophrenia - phenotype - genotype - genetic association study

• Literatur

• 1 Cardno AG, Gottesman II. Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics. Am J Med Genet 2000; 97: 12-17
• 2 Lichtenstein P, Yip BH, Bjork C et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 2009; 373: 234-239
• 3 Cardno AG, Marshall EJ, Coid B et al. Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch Gen Psychiatry 1999; 56: 162-168
• 4 Franzek E, Beckmann H. Different genetic background of schizophrenia spectrum psychoses: a twin study. Am J Psychiatry 1998; 155: 76-83
• 5 van Os J, Kenis G, Rutten BP. The environment and schizophrenia. Nature 2010; 468: 203-212
• 6 Svrakic DM, Zorumski CF, Svrakic NM et al. Risk architecture of schizophrenia: the role of epigenetics. Curr Opin Psychiatry 2013; 2: 188-195
• 7 O’Donovan MC, Craddock N, Norton N et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet 2008; 40: 1053-1055
• 8 Purcell SM, Wray NR, Stone JL et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009; 460: 748-752
• 9 Shi J, Levinson DF, Duan J et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 2009; 460: 753-757
• 10 Stefansson H, Ophoff RA, Steinberg S et al. Common variants conferring risk of schizophrenia. Nature 2009; 460: 744-747
• 11 Papiol S, Malzahn D, Kästner A et al. Dissociation of accumulated genetic risk and disease severity in patients with schizophrenia. Translational Psychiatry 2011; 1: e45
• 12 Chubb JE, Bradshaw NJ, Soares DC et al. The DISC locus in psychiatric illness. Mol Psychiatry 2008; 13: 36-64
• 13 Ribbe K, Friedrichs H, Begemann M et al. The cross-sectional GRAS sample: A comprehensive phenotypical data collection of schizophrenic patients. BMC Psychiatry 2010; 10: 91
• 14 Begemann M, Grube S, Papiol S et al. Modification of cognitive performance in schizophrenia by complexin 2 gene polymorphisms. Arch Gen Psychiatry 2010; 67: 879-888
• 15 Grube S, Gerchen MF, Adamcio B et al. A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in schizophrenia. EMBO Mol Med 2011; 3: 309-319
• 16 Papiol S, Begemann M, Rosenberger A et al. A phenotype-based genetic association study reveals the contribution of neuregulin1 gene variants to age of onset and positive symptom severity in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2011; 156B: 340-345
• 17 Hagemeyer N, Goebbels S, Papiol S et al. A myelin gene causative of a catatonia-depression syndrome upon aging. EMBO Mol Med 2012; 4: 528-539