Behavioural and functional evidence revealing the role of RBFOX1 variation in multiple psychiatric disorders and traits.

Autor: O'Leary A; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany. aet.oleary@kgu.de.; Department of Neuropscyhopharmacology, Institute of Chemistry, University of Tartu, Tartu, Estonia. aet.oleary@kgu.de., Fernàndez-Castillo N; Department de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, and Institut de Biomedicina de la Universitat de Barcelona (IBUB); Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII); Madrid, Spain; Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Barcelona, Catalonia, Spain., Gan G; Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany., Yang Y; Department of Psychiatry and Psychotherapy and Center for Mind, Brain and Behavior - CMBB, University of Marburg, Marburg, Germany., Yotova AY; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany.; Institute of Cell Biology and Neuroscience, Faculty of Biosciences, Goethe University Frankfurt, Frankfurt am Main, Germany., Kranz TM; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany., Grünewald L; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany., Freudenberg F; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany., Antón-Galindo E; Department de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, and Institut de Biomedicina de la Universitat de Barcelona (IBUB); Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII); Madrid, Spain; Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Barcelona, Catalonia, Spain., Cabana-Domínguez J; Department de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, and Institut de Biomedicina de la Universitat de Barcelona (IBUB); Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII); Madrid, Spain; Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Barcelona, Catalonia, Spain., Harneit A; Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany., Schweiger JI; Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany., Schwarz K; Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany., Ma R; Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany., Chen J; Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany., Schwarz E; Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany., Rietschel M; Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany., Tost H; Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany., Meyer-Lindenberg A; Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany., Pané-Farré CA; Department of Psychiatry and Psychotherapy and Center for Mind, Brain and Behavior - CMBB, University of Marburg, Marburg, Germany.; Department of Biological and Clinical Psychology/Psychotherapy, University of Greifswald, Greifswald, Germany., Kircher T; Department of Psychiatry and Psychotherapy and Center for Mind, Brain and Behavior - CMBB, University of Marburg, Marburg, Germany., Hamm AO; Department of Biological and Clinical Psychology/Psychotherapy, University of Greifswald, Greifswald, Germany., Burguera D; Department of Zoology, Charles University, Prague, Czech Republic., Mota NR; Department of Human Genetics and Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands., Franke B; Department of Human Genetics and Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands., Schweiger S; Mainz University Medical Center, Institute of Human Genetics, Mainz, Germany., Winter J; Mainz University Medical Center, Institute of Human Genetics, Mainz, Germany., Heinz A; Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Berlin, Germany., Erk S; Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Berlin, Germany., Romanczuk-Seiferth N; Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Berlin, Germany., Walter H; Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Berlin, Germany., Ströhle A; Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Berlin, Germany., Fehm L; Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany., Fydrich T; Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany., Lueken U; Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany., Weber H; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany.; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University of Würzburg, Würzburg, Germany., Lang T; Christoph-Dornier-Foundation for Clinical Psychology, Institute for Clinical Psychology Bremen; Bremen, Germany and Department for Psychology & Methods, Jacobs University Bremen, Bremen, Germany., Gerlach AL; Clinical Psychology and Psychotherapy, University of Cologne, Cologne, Germany., Nöthen MM; Institute of Human Genetics, School of Medicine and University Hospital Bonn, University of Bonn, Bonn, Germany., Alpers GW; Department of Psychology, School of Social Sciences, University of Mannheim, Mannheim, Germany., Arolt V; Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany., Witt S; Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany., Richter J; Department of Biological and Clinical Psychology/Psychotherapy, University of Greifswald, Greifswald, Germany.; Department of Experimental Psychopathology, University of Hildesheim, Hildesheim, Germany., Straube B; Department of Psychiatry and Psychotherapy and Center for Mind, Brain and Behavior - CMBB, University of Marburg, Marburg, Germany., Cormand B; Department de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, and Institut de Biomedicina de la Universitat de Barcelona (IBUB); Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII); Madrid, Spain; Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Barcelona, Catalonia, Spain., Slattery DA; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany., Reif A; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2022 Nov; Vol. 27 (11), pp. 4464-4473. Date of Electronic Publication: 2022 Aug 10.
DOI: 10.1038/s41380-022-01722-4
Abstrakt: Common variation in the gene encoding the neuron-specific RNA splicing factor RNA Binding Fox-1 Homolog 1 (RBFOX1) has been identified as a risk factor for several psychiatric conditions, and rare genetic variants have been found causal for autism spectrum disorder (ASD). Here, we explored the genetic landscape of RBFOX1 more deeply, integrating evidence from existing and new human studies as well as studies in Rbfox1 knockout mice. Mining existing data from large-scale studies of human common genetic variants, we confirmed gene-based and genome-wide association of RBFOX1 with risk tolerance, major depressive disorder and schizophrenia. Data on six mental disorders revealed copy number losses and gains to be more frequent in ASD cases than in controls. Consistently, RBFOX1 expression appeared decreased in post-mortem frontal and temporal cortices of individuals with ASD and prefrontal cortex of individuals with schizophrenia. Brain-functional MRI studies demonstrated that carriers of a common RBFOX1 variant, rs6500744, displayed increased neural reactivity to emotional stimuli, reduced prefrontal processing during cognitive control, and enhanced fear expression after fear conditioning, going along with increased avoidance behaviour. Investigating Rbfox1 neuron-specific knockout mice allowed us to further specify the role of this gene in behaviour. The model was characterised by pronounced hyperactivity, stereotyped behaviour, impairments in fear acquisition and extinction, reduced social interest, and lack of aggression; it provides excellent construct and face validity as an animal model of ASD. In conclusion, convergent translational evidence shows that common variants in RBFOX1 are associated with a broad spectrum of psychiatric traits and disorders, while rare genetic variation seems to expose to early-onset neurodevelopmental psychiatric disorders with and without developmental delay like ASD, in particular. Studying the pleiotropic nature of RBFOX1 can profoundly enhance our understanding of mental disorder vulnerability.
(© 2022. The Author(s).)
Databáze: MEDLINE
Externí odkaz: