Behavioural and functional evidence revealing the role of RBFOX1 variation in multiple psychiatric disorders and traits
Por:
O'Leary, A, Fernandez-Castillo N, Gan, G, Yang, YB, Yotova, AY, Kranz, TM, Grunewald, L, Freudenberg, F, Anton-Galindo, E, Cabana-Domínguez J, Harneit, A, Schweiger, JI, Schwarz, K, Ma, R, Chen, JF, Schwarz, E, Rietschel, M, Tost, H, Meyer-Lindenberg, A, Pane-Farre, CA, Kircher, T, Hamm, AO, Burguera, D, Mota, NR, Franke, B, Schweiger, S, Winter, J, Heinz, A, Erk, S, Romanczuk-Seiferth, N, Walter, H, Ströhle A, Fehm, L, Fydrich, T, Lueken, U, Weber, H, Lang, T, Gerlach, AL, Nöthen MM, Alpers, GW, Arolt, V, Witt, S, Richter, J, Straube, B, Cormand B, Slattery, DA and Reif, A
Publicada:
1 nov 2022
Ahead of Print:
1 ago 2022
Resumen:
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.
Filiaciones:
O'Leary, A:
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany.
Department of Neuropscyhopharmacology, Institute of Chemistry, University of Tartu, Tartu, Estonia.
Goethe Univ Frankfurt, Univ Hosp, Dept Psychiat Psychosomat Med & Psychotherapy, Frankfurt, Germany
Univ Tartu, Inst Chem, Dept Neuropscyhopharmacol, Tartu, Estonia
Fernandez-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
Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, Mannheim, Germany
Yang, YB:
Department of Psychiatry and Psychotherapy and Center for Mind, Brain and Behavior - CMBB, University of Marburg, Marburg, Germany
Univ Marburg, Dept Psychiat & Psychotherapy, Marburg, Germany
Univ Marburg, Ctr Mind Brain & Behav CMBB, 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
Goethe Univ Frankfurt, Univ Hosp, Dept Psychiat Psychosomat Med & Psychotherapy, Frankfurt, Germany
Goethe Univ Frankfurt, Fac Biosci, Inst Cell Biol & Neurosci, Frankfurt, Germany
Kranz, TM:
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany
Goethe Univ Frankfurt, Univ Hosp, Dept Psychiat Psychosomat Med & Psychotherapy, Frankfurt, Germany
Grunewald, L:
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany
Goethe Univ Frankfurt, Univ Hosp, Dept Psychiat Psychosomat Med & Psychotherapy, Frankfurt, Germany
Freudenberg, F:
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany
Goethe Univ Frankfurt, Univ Hosp, Dept Psychiat Psychosomat Med & Psychotherapy, Frankfurt, Germany
Anton-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
Univ Barcelona, Fac Biol, Dept Genet Microbiol & Estadist, Barcelona, Catalonia, Spain
Univ Barcelona IBUB, Inst Biomed, Barcelona, Catalonia, Spain
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain
Inst Recerca St Joan Deu IR SJD, 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
Univ Barcelona, Fac Biol, Dept Genet Microbiol & Estadist, Barcelona, Catalonia, Spain
Univ Barcelona IBUB, Inst Biomed, Barcelona, Catalonia, Spain
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain
Inst Recerca St Joan Deu IR SJD, Barcelona, Catalonia, Spain
Harneit, A:
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, Mannheim, Germany
Schweiger, JI:
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, Mannheim, Germany
Schwarz, K:
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, Mannheim, Germany
Ma, R:
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, Mannheim, Germany
Chen, JF:
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, Mannheim, Germany
Schwarz, E:
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, Mannheim, Germany
Rietschel, M:
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, Mannheim, Germany
Tost, H:
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, Mannheim, Germany
Meyer-Lindenberg, A:
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, Mannheim, Germany
Pane-Farre, 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
Univ Marburg, Dept Psychiat & Psychotherapy, Marburg, Germany
Univ Marburg, Ctr Mind Brain & Behav CMBB, Marburg, Germany
Univ Greifswald, Dept Biol & Clin Psychol Psychotherapy, Greifswald, Germany
Kircher, T:
Department of Psychiatry and Psychotherapy and Center for Mind, Brain and Behavior - CMBB, University of Marburg, Marburg, Germany
Univ Marburg, Dept Psychiat & Psychotherapy, Marburg, Germany
Univ Marburg, Ctr Mind Brain & Behav CMBB, Marburg, Germany
Hamm, AO:
Department of Biological and Clinical Psychology/Psychotherapy, University of Greifswald, Greifswald, Germany
Univ Greifswald, Dept Biol & Clin Psychol Psychotherapy, Greifswald, Germany
Burguera, D:
Department of Zoology, Charles University, Prague, Czech Republic
Charles Univ Prague, Dept Zool, 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
Radboud Univ Nijmegen Med Ctr, Donders Inst Brain Cognit & Behav, Dept Human Genet, Nijmegen, Netherlands
Radboud Univ Nijmegen Med Ctr, Donders Inst Brain Cognit & Behav, Dept Psychiat, 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
Radboud Univ Nijmegen Med Ctr, Donders Inst Brain Cognit & Behav, Dept Human Genet, Nijmegen, Netherlands
Radboud Univ Nijmegen Med Ctr, Donders Inst Brain Cognit & Behav, Dept Psychiat, Nijmegen, Netherlands
Schweiger, S:
Mainz University Medical Center, Institute of Human Genetics, Mainz, Germany
Mainz Univ, Inst Human Genet, Med Ctr, Mainz, Germany
Winter, J:
Mainz University Medical Center, Institute of Human Genetics, Mainz, Germany
Mainz Univ, Inst Human Genet, Med Ctr, Mainz, Germany
Heinz, A:
Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Berlin, Germany
Charite Univ Med Berlin, Dept Psychiat & Psychotherapy, Berlin, Germany
Erk, S:
Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Berlin, Germany
Charite Univ Med Berlin, Dept Psychiat & Psychotherapy, Berlin, Germany
Romanczuk-Seiferth, N:
Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Berlin, Germany
Charite Univ Med Berlin, Dept Psychiat & Psychotherapy, Berlin, Germany
Walter, H:
Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Berlin, Germany
Charite Univ Med Berlin, Dept Psychiat & Psychotherapy, 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
Humboldt Univ, Dept Psychol, Berlin, Germany
Fydrich, T:
Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany
Humboldt Univ, Dept Psychol, Berlin, Germany
Lueken, U:
Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany
Humboldt Univ, Dept Psychol, 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
Goethe Univ Frankfurt, Univ Hosp, Dept Psychiat Psychosomat Med & Psychotherapy, Frankfurt, Germany
Univ Wurzburg, Dept Psychiat Psychosomat Med & Psychotherapy, Wurzburg, 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
Christoph Dornier Fdn Clin Psychol, Inst Clin Psychol Bremen, Bremen, Germany
Jacobs Univ Bremen, Dept Psychol & Methods, Bremen, Germany
Gerlach, AL:
Clinical Psychology and Psychotherapy, University of Cologne, Cologne, Germany
Univ Cologne, Clin Psychol & Psychotherapy, 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
Univ Mannheim, Sch Social Sci, Dept Psychol, Mannheim, Germany
Arolt, V:
Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany
Univ Munster, Dept Psychiat & Psychotherapy, Munster, Germany
Witt, S:
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, 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
Univ Greifswald, Dept Biol & Clin Psychol Psychotherapy, Greifswald, Germany
Univ Hildesheim, Dept Expt Psychopathol, Hildesheim, Germany
Straube, B:
Department of Psychiatry and Psychotherapy and Center for Mind, Brain and Behavior - CMBB, University of Marburg, Marburg, Germany
Univ Marburg, Dept Psychiat & Psychotherapy, Marburg, Germany
Univ Marburg, Ctr Mind Brain & Behav CMBB, 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
Univ Barcelona, Fac Biol, Dept Genet Microbiol & Estadist, Barcelona, Catalonia, Spain
Univ Barcelona IBUB, Inst Biomed, Barcelona, Catalonia, Spain
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain
Inst Recerca St Joan Deu IR SJD, Barcelona, Catalonia, Spain
Slattery, DA:
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany
Goethe Univ Frankfurt, Univ Hosp, Dept Psychiat Psychosomat Med & Psychotherapy, Frankfurt, Germany
Reif, A:
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany
Goethe Univ Frankfurt, Univ Hosp, Dept Psychiat Psychosomat Med & Psychotherapy, Frankfurt, Germany
Univ Bonn, Sch Med, Inst Human Genet, Bonn, Germany
Univ Bonn, Univ Hosp Bonn, Bonn, Germany
Green Submitted, hybrid
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