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

D Mielenz, , M Reichel, T Jia, E B Quinlan, T Stöckl, M Mettang, D Zilske, E Kirmizi-Alsan, P Schönberger, M Praetner, S E Huber, D Amato, M Schwarz, P Purohit, S Brachs, J Spranger, A Hess, C Büttner, A B Ekici, F Perez-Branguli, B Winner, V Rauschenberger, T Banaschewski, A L W Bokde, C Büchel, P J Conrod, S Desrivières, H Flor, V Frouin, J Gallinat, H Garavan, P Gowland, A Heinz, J-L Martinot, H Lemaitre, F Nees, T Paus, M N Smolka, A Schambony, T Bäuerle, V Eulenburg, C Alzheimer, A Lourdusamy, G Schumann, C P Müller
Mol Psychiatry. 2017-04-11; 23(5): 1303-1319
DOI: 10.1038/mp.2017.63


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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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