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.

Christoph Dornier Foundation for Clinical Psychology Institute for Clinical Psychology Bremen; Bremen Germany and Department for Psychology and Methods Jacobs University Bremen Bremen Germany

Clinical Psychology and Psychotherapy University of Cologne Cologne Germany

Department de Genètica Microbiologia i Estadística Facultat de Biologia Universitat de Barcelona and Institut de Biomedicina de la Universitat de Barcelona Esplugues de Llobregat Barcelona Catalonia Spain

Department of Biological and Clinical Psychology Psychotherapy University of Greifswald Greifswald Germany

Department of Experimental Psychopathology University of Hildesheim Hildesheim Germany

Department of Genetic Epidemiology in Psychiatry Central Institute of Mental Health Medical Faculty Mannheim University of Heidelberg Mannheim Germany

Department of Human Genetics and Department of Psychiatry Donders Institute for Brain Cognition and Behaviour Radboud University Medical Center Nijmegen Netherlands

Department of Neuropscyhopharmacology Institute of Chemistry University of Tartu Tartu Estonia

Department of Psychiatry and Psychotherapy and Center for Mind Brain and Behavior CMBB University of Marburg Marburg Germany

Department of Psychiatry and Psychotherapy Central Institute of Mental Health Medical Faculty Mannheim University of Heidelberg Mannheim Germany

Department of Psychiatry and Psychotherapy Charité University Medicine Berlin Berlin Germany

Department of Psychiatry and Psychotherapy University of Münster Münster Germany

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

Department of Psychology Humboldt Universität zu Berlin Berlin Germany

Department of Psychology School of Social Sciences University of Mannheim Mannheim Germany

Department of Zoology Charles University Prague Czech Republic

Institute of Cell Biology and Neuroscience Faculty of Biosciences Goethe University Frankfurt Frankfurt am Main Germany

Institute of Human Genetics School of Medicine and University Hospital Bonn University of Bonn Bonn Germany

Mainz University Medical Center Institute of Human Genetics Mainz Germany

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