O'Leary, Aet ORCID: 0000-0001-6783-4729, Fernandez-Castillo, Noelia ORCID: 0000-0001-9948-0312, Gan, Gabriela, Yang, Yunbo, Yotova, Anna Y. ORCID: 0000-0002-4792-8696, Kranz, Thorsten M., Gruenewald, Lena, Freudenberg, Florian ORCID: 0000-0003-1438-3850, Anton-Galindo, Ester, Cabana-Dominguez, Judit, Harneit, Anais, Schweiger, Janina, I, Schwarz, Kristina, Ma, Ren, Chen, Junfang, Schwarz, Emanuel, Rietschel, Marcella, Tost, Heike, Meyer-Lindenberg, Andreas, Pane-Farre, Christiane A., Kircher, Tilo ORCID: 0000-0002-2514-2625, Hamm, Alfons O., Burguera, Demian ORCID: 0000-0001-8627-1634, Mota, Nina Roth, Franke, Barbara ORCID: 0000-0003-4375-6572, Schweiger, Susann, Winter, Jennifer, Heinz, Andreas ORCID: 0000-0001-5405-9065, Erk, Susanne ORCID: 0000-0003-0961-3543, Romanczuk-Seiferth, Nina ORCID: 0000-0002-6931-269X, Walter, Henrik ORCID: 0000-0002-9403-6121, Stroehle, Andreas, Fehm, Lydia, Fydrich, Thomas, Lueken, Ulrike, Weber, Heike, Lang, Thomas, Gerlach, Alexander L., Noethen, Markus M., Alpers, Georg W. ORCID: 0000-0001-9896-5158, Arolt, Volker, Witt, Stephanie, Richter, Jan, Straube, Benjamin, Cormand, Bru, Slattery, David A. and Reif, Andreas (2022). Behavioural and functional evidence revealing the role of RBFOX1 variation in multiple psychiatric disorders and traits. Mol. Psychiatr., 27 (11). S. 4464 - 4474. LONDON: SPRINGERNATURE. ISSN 1476-5578

Full text not available from this repository.

Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
O'Leary, AetUNSPECIFIEDorcid.org/0000-0001-6783-4729UNSPECIFIED
Fernandez-Castillo, NoeliaUNSPECIFIEDorcid.org/0000-0001-9948-0312UNSPECIFIED
Gan, GabrielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yang, YunboUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yotova, Anna Y.UNSPECIFIEDorcid.org/0000-0002-4792-8696UNSPECIFIED
Kranz, Thorsten M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gruenewald, LenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Freudenberg, FlorianUNSPECIFIEDorcid.org/0000-0003-1438-3850UNSPECIFIED
Anton-Galindo, EsterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cabana-Dominguez, JuditUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Harneit, AnaisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schweiger, Janina, IUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwarz, KristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ma, RenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, JunfangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwarz, EmanuelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rietschel, MarcellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tost, HeikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meyer-Lindenberg, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pane-Farre, Christiane A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kircher, TiloUNSPECIFIEDorcid.org/0000-0002-2514-2625UNSPECIFIED
Hamm, Alfons O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burguera, DemianUNSPECIFIEDorcid.org/0000-0001-8627-1634UNSPECIFIED
Mota, Nina RothUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Franke, BarbaraUNSPECIFIEDorcid.org/0000-0003-4375-6572UNSPECIFIED
Schweiger, SusannUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Winter, JenniferUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heinz, AndreasUNSPECIFIEDorcid.org/0000-0001-5405-9065UNSPECIFIED
Erk, SusanneUNSPECIFIEDorcid.org/0000-0003-0961-3543UNSPECIFIED
Romanczuk-Seiferth, NinaUNSPECIFIEDorcid.org/0000-0002-6931-269XUNSPECIFIED
Walter, HenrikUNSPECIFIEDorcid.org/0000-0002-9403-6121UNSPECIFIED
Stroehle, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fehm, LydiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fydrich, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lueken, UlrikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weber, HeikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lang, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerlach, Alexander L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noethen, Markus M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alpers, Georg W.UNSPECIFIEDorcid.org/0000-0001-9896-5158UNSPECIFIED
Arolt, VolkerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Witt, StephanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richter, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Straube, BenjaminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cormand, BruUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Slattery, David A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reif, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-696742
DOI: 10.1038/s41380-022-01722-4
Journal or Publication Title: Mol. Psychiatr.
Volume: 27
Number: 11
Page Range: S. 4464 - 4474
Date: 2022
Publisher: SPRINGERNATURE
Place of Publication: LONDON
ISSN: 1476-5578
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENETIC RISK; INTERMEDIATE PHENOTYPE; PANIC DISORDER; CONNECTIVITY; POLYMORPHISM; MECHANISMS; CORTEX; MODELMultiple languages
Biochemistry & Molecular Biology; Neurosciences; PsychiatryMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69674

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item