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

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Dirk Mielenz, Martin Reichel, Tianye Jia, Erin Burke Quinlan, Thomas Stöckl, Melissa Mettang, Daniel Zilske, Elif Kirmizi-Alsan, Penelope Schönberger, Marc Praetner, Sabine E. Huber, Davide Amato, Marc Schwarz, Pavitra Purohit, Sebastian Brachs, Joachim Spranger, Andreas Hessenthaler, Christian Büttner, Arif B. Ekici, Francesc Perez-Branguli & 26 more Beate Winner, Verena Rauschenberger, Tobias Banaschewski, Arun L W Bokde, Christian Buechel, Patricia J. Conrod, Sylvane Desrivieres, Herta Flor, Vincent Frouin, Juergen Gallinat, Hugh Garavan, Penny Gowland, Andreas Heinz, Jean-Luc Martinot, Herve Lemaitre, Frauke Nees, Tomas Paus, Michael N. Smolka, The IMAGEN Consortium, Alexandra Schambony, Tobias Bäuerle, Volker Eulenburg, Christian Alzheimer, Anbarasu Lourdusamy, Gunter Schumann, Christian P. Mueller

Original languageEnglish
JournalMolecular Psychiatry
Early online date11 Apr 2017
DOIs
Accepted/In press10 Feb 2017
E-pub ahead of print11 Apr 2017

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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

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