title: EFhd2/Swiprosin-1 is a common genetic determinator for sensation-seeking/low anxiety and alcohol addiction.
abstract: In many societies, the majority of adults regularly consume alcohol. However, only a small proportion develops alcohol addiction. Individuals at risk often show a high sensation-seeking/low-anxiety behavioural phenotype. Here we asked which role EF hand domain containing 2 (EFhd2; Swiprosin-1) plays in the control of alcohol addiction-associated behaviours. EFhd2 knockout (KO) mice drink more alcohol than controls and spontaneously escalate their consumption. This coincided with a sensation-seeking and low-anxiety phenotype. A reversal of the behavioural phenotype with β-carboline, an anxiogenic inverse benzodiazepine receptor agonist, normalized alcohol preference in EFhd2 KO mice, demonstrating an EFhd2-driven relationship between personality traits and alcohol preference. These findings were confirmed in a human sample where we observed a positive association of the EFhd2 single-nucleotide polymorphism rs112146896 with lifetime drinking and a negative association with anxiety in healthy adolescents. The lack of EFhd2 reduced extracellular dopamine levels in the brain, but enhanced responses to alcohol. In confirmation, gene expression analysis revealed reduced tyrosine hydroxylase expression and the regulation of genes involved in cortex development, Eomes and Pax6, in EFhd2 KO cortices. These findings were corroborated in Xenopus tadpoles by EFhd2 knockdown. Magnetic resonance imaging (MRI) in mice showed that a lack of EFhd2 reduces cortical volume in adults. Moreover, human MRI confirmed the negative association between lifetime alcohol drinking and superior frontal gyrus volume. We propose that EFhd2 is a conserved resilience factor against alcohol consumption and its escalation, working through Pax6/Eomes. Reduced EFhd2 function induces high-risk personality traits of sensation-seeking/low anxiety associated with enhanced alcohol consumption, which may be related to cortex function.
authors.affiliation: Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger-Center, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Mielenz
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: M
authors.identifier: 0000-0001-7886-2784
authors.initials: M
authors.lastname: Reichel
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College London, London, UK.
authors.forename: T
authors.identifier: 0000-0001-5399-2953
authors.initials: T
authors.lastname: Jia
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College London, London, UK.
authors.forename: E B
authors.initials: EB
authors.lastname: Quinlan
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Stöckl
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Mettang
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Zilske
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Kirmizi-Alsan
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Schönberger
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Praetner
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: S E
authors.initials: SE
authors.lastname: Huber
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Amato
authors.affiliation: Institute of Radiology, University Medical Center Erlangen, Erlangen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schwarz
authors.affiliation: Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger-Center, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Purohit
authors.affiliation: Department of Endocrinology, Diabetes and Nutrition, Center for Cardiovascular Research, Charité - University School of Medicine, Berlin, Germany.|German Center for Cardiovascular Research, DZHK Partner site Berlin, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Brachs
authors.affiliation: Department of Endocrinology, Diabetes and Nutrition, Center for Cardiovascular Research, Charité - University School of Medicine, Berlin, Germany.|German Center for Cardiovascular Research, DZHK Partner site Berlin, Berlin, Germany.
authors.forename: J
authors.identifier: 0000-0002-8900-4467
authors.initials: J
authors.lastname: Spranger
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Hess
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Büttner
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: A B
authors.initials: AB
authors.lastname: Ekici
authors.affiliation: IZKF Nachwuchsgruppe III, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Perez-Branguli
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.|IZKF Nachwuchsgruppe III, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Winner
authors.affiliation: Department of Biology, Developmental Biology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Rauschenberger
authors.affiliation: Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Banaschewski
authors.affiliation: Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
authors.forename: A L W
authors.initials: ALW
authors.lastname: Bokde
authors.affiliation: Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Büchel
authors.affiliation: Department of Psychiatry, Universite de Montreal, CHU Sainte-Justine Hospital, Montreal, QC, Canada.|Department of Psychological Medicine and Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Conrod
authors.affiliation: Medical Research Council - Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Desrivières
authors.affiliation: Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Flor
authors.affiliation: Neurospin, Commissariat à l'Energie Atomique, CEA-Saclay Center, Paris, France.
authors.forename: V
authors.identifier: 0000-0001-9360-6623
authors.initials: V
authors.lastname: Frouin
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Gallinat
authors.affiliation: Departments of Psychiatry and Psychology, University of Vermont, Burlington, VT, USA.
authors.forename: H
authors.initials: H
authors.lastname: Garavan
authors.affiliation: Sir Peter Mansfield Imaging Centre School of Physics and Astronomy, University of Nottingham, University Park, Nottingham, UK.
authors.forename: P
authors.initials: P
authors.lastname: Gowland
authors.affiliation: Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité, Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Heinz
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, INSERM Unit 1000 "Neuroimaging & Psychiatry", University Paris Sud, University Paris Descartes - Sorbonne Paris Cité and Maison de Solenn, Paris, France.
authors.forename: J-L
authors.initials: JL
authors.lastname: Martinot
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, INSERM Unit 1000 "Neuroimaging & Psychiatry", Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre and Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: H
authors.initials: H
authors.lastname: Lemaitre
authors.affiliation: Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Nees
authors.affiliation: Rotman Research Institute, Baycrest and Departments of Psychology and Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Paus
authors.affiliation: Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden, Dresden, Germany.
authors.forename: M N
authors.initials: MN
authors.lastname: Smolka
authors.affiliation: Department of Biology, Developmental Biology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Schambony
authors.affiliation: Institute of Radiology, University Medical Center Erlangen, Erlangen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Bäuerle
authors.affiliation: Institute of Biochemistry, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: V
authors.identifier: 0000-0002-4878-5746
authors.initials: V
authors.lastname: Eulenburg
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität, Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Alzheimer
authors.affiliation: Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham, UK.
authors.forename: A
authors.initials: A
authors.lastname: Lourdusamy
authors.affiliation: Medical Research Council - Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Schumann
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: C P
authors.initials: CP
authors.lastname: Müller
mesh_terms: D000293:Adolescent; D000328:Adult; D000428:Alcohol Drinking / Q000235:genetics; D000437:Alcoholism / Q000235:genetics*; D000818:Animals; D001007:Anxiety / Q000235:genetics*; D001008:Anxiety Disorders / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide; D012309:Risk-Taking; D014982:Xenopus laevis
chemical_list: D002135:Calcium-Binding Proteins; C502299:EFHD2 protein, human; C530752:EFHD2 protein, mouse