EFhd2/Swiprosin-1 is a common genetic determinator for sensation-seeking/low anxiety and alcohol addiction

Journal article

Publication Details

Author(s): Mielenz D, Reichel M, Jia T, Quinlan EB, Stöckl T, Mettang M, Zilske D, kirmizi Alsan E, Schoenberger P, Praetner M, Huber S, Amato D, Schwarz M, Purohit P, Brachs S, Spranger J, Heß A, Büttner C, Ekici AB, Perez-Branguli F, Winner B, Rauschenberger V, Banaschewski T, Bokde ALW, Buechel C, Conrod PJ, Desrivieres S, Flor H, Frouin V, Gallinat J, Garavan H, Gowland P, Heinz A, Martinot JL, Lemaitre H, Nees F, Paus T, Smolka MN, Schambony A, Bäuerle T, Eulenburg V, Alzheimer C, Lourdusamy A, Schumann G, Müller CP
Journal: Molecular Psychiatry
Publication year: 2018
Volume: 23
Journal issue: 5
Pages range: 1303-1319
ISSN: 1359-4184


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.

FAU Authors / FAU Editors

Alzheimer, Christian Prof. Dr.
Lehrstuhl für Physiologie
Amato, Davide PD Dr.
Müller, Christian P. Prof. Dr.
Psychiatrische und Psychotherapeutische Klinik
Bäuerle, Tobias Prof. Dr.
Professur für Multimodale Bildgebung in der präklinischen Forschung
Büttner, Christian
Rauschenberger, Verena
Lehrstuhl für Humangenetik
Ekici, Arif Bülent Dr. rer. nat.
Humangenetisches Institut
Eulenburg, Volker PD Dr.
Lehrstuhl für Biochemie und Molekulare Medizin
Heß, Andreas Prof. Dr.
Lehrstuhl für Pharmakologie und Toxikologie
Huber, Sabine
Professur für Suchtmedizin
kirmizi Alsan, Elif
Professur für Suchtmedizin
Mielenz, Dirk Prof. Dr.
Medizinische Fakultät
Professur für Suchtmedizin
Lehrstuhl für Entwicklungsbiologie
Reichel, Martin PD Dr.
Psychiatrische und Psychotherapeutische Klinik
Schambony, Alexandra Prof. Dr.
Lehrstuhl für Entwicklungsbiologie
Schwarz, Martin
Professur für Experimentelle Augenheilkunde
Stöckl, Thomas Dr. med.
Psychiatrische und Psychotherapeutische Klinik
Winner, Beate Prof. Dr.
Humangenetisches Institut
Zilske, Daniel
Professur für Suchtmedizin

External institutions with authors

Centre CEA de Saclay (Essonne)
Charité - Universitätsmedizin Berlin
King’s College London
Ruprecht-Karls-Universität Heidelberg
Technische Universität Dresden
Trinity College Dublin
Universitätsklinikum Hamburg-Eppendorf (UKE)
Université de Montréal
University of Nottingham
University of Paris 11 - Paris-Sud / Université Paris XI Paris-Sud
University of Paris 5 - René Descartes / Université Paris V René Descartes
University of Toronto
University of Vermont

How to cite

Mielenz, D., Reichel, M., Jia, T., Quinlan, E.B., Stöckl, T., Mettang, M.,... Müller, C.P. (2018). EFhd2/Swiprosin-1 is a common genetic determinator for sensation-seeking/low anxiety and alcohol addiction. Molecular Psychiatry, 23(5), 1303-1319. https://dx.doi.org/10.1038/mp.2017.63

Mielenz, Dirk, et al. "EFhd2/Swiprosin-1 is a common genetic determinator for sensation-seeking/low anxiety and alcohol addiction." Molecular Psychiatry 23.5 (2018): 1303-1319.


Last updated on 2019-20-07 at 07:21