Mouse and human genetic analyses associate Kalirin with ventral striatal activation during impulsivity and with alcohol misuse

Pe�a-Oliver, Yolanda; Carvalho, Fabiana M.; Sanchez-Roige, Sandra; Quinlan, Erin Burke; Jia, Tianye; Walker-Tilley, Tom; Rulten, Stuart L.; Pearl, Frances M. G.; Banaschewski, Tobias; Barker, Gareth J.; Bokde, Arun L. W.; B�chel, Christian; Conrod, Patricia J.; Flor, Herta; Gallinat, J�rgen; Garavan, Hugh; Heinz, Andreas; Gowland, Penny A.; Paillere Martinot, Marie-Laure; Paus, Tom�; Rietschel, Marcella; Robbins, Trevor W.; Smolka, Michael N.; Schumann, Gunter; Stephens, David N.

doi:10.3389/fgene.2016.00052

Mouse and human genetic analyses associate Kalirin with ventral striatal activation during impulsivity and with alcohol misuse

Pe�a-Oliver, Yolanda; Carvalho, Fabiana M.; Sanchez-Roige, Sandra; Quinlan, Erin Burke; Jia, Tianye; Walker-Tilley, Tom; Rulten, Stuart L.; Pearl, Frances M. G.; Banaschewski, Tobias; Barker, Gareth J.; Bokde, Arun L. W.; B�chel, Christian; Conrod, Patricia J.; Flor, Herta; Gallinat, J�rgen; Garavan, Hugh; Heinz, Andreas; Gowland, Penny A.; Paillere Martinot, Marie-Laure; Paus, Tom�; Rietschel, Marcella; Robbins, Trevor W.; Smolka, Michael N.; Schumann, Gunter; Stephens, David N.

Authors

Yolanda Pe�a-Oliver

Fabiana M. Carvalho

Sandra Sanchez-Roige

Erin Burke Quinlan

Tianye Jia

Tom Walker-Tilley

Stuart L. Rulten

Frances M. G. Pearl

Tobias Banaschewski

Gareth J. Barker

Arun L. W. Bokde

Christian B�chel

Patricia J. Conrod

Herta Flor

J�rgen Gallinat

Hugh Garavan

Andreas Heinz

Penny A. Gowland

Marie-Laure Paillere Martinot

Tom� Paus

Marcella Rietschel

Trevor W. Robbins

Michael N. Smolka

Gunter Schumann

David N. Stephens

Abstract

Impulsivity is associated with a spectrum of psychiatric disorders including drug addiction. To investigate genetic associations with impulsivity and initiation of drug taking, we took a two-step approach. First, we identified genes whose expression level in prefrontal cortex, striatum and accumbens were associated with impulsive behavior in the 5-choice serial reaction time task across 10 BXD recombinant inbred (BXD RI) mouse strains and their progenitor C57BL/6J and DBA2/J strains. Behavioral data were correlated with regional gene expression using GeneNetwork (www.genenetwork.org), to identify 44 genes whose probability of association with impulsivity exceeded a false discovery rate of < 0.05. We then interrogated the IMAGEN database of 1423 adolescents for potential associations of SNPs in human homologs of those genes identified in the mouse study, with brain activation during impulsive performance in the Monetary Incentive Delay task, and with novelty seeking scores from the Temperament and Character Inventory, as well as alcohol experience. There was a significant overall association between the human homologs of impulsivity-related genes and percentage of premature responses in the MID task and with fMRI BOLD-response in ventral striatum (VS) during reward anticipation. In contrast, no significant association was found between the polygenic scores and anterior cingulate cortex activation. Univariate association analyses revealed that the G allele (major) of the intronic SNP rs6438839 in the KALRN gene was significantly associated with increased VS activation. Additionally, the A-allele (minor) of KALRN intronic SNP rs4634050, belonging to the same haplotype block, was associated with increased frequency of binge drinking.

Citation

Peña-Oliver, Y., Carvalho, F. M., Sanchez-Roige, S., Quinlan, E. B., Jia, T., Walker-Tilley, T., …Stephens, D. N. (2016). Mouse and human genetic analyses associate Kalirin with ventral striatal activation during impulsivity and with alcohol misuse. Frontiers in Genetics, 7, Article 52. https://doi.org/10.3389/fgene.2016.00052

Journal Article Type	Article
Acceptance Date	Mar 21, 2016
Publication Date	Apr 7, 2016
Deposit Date	Jan 5, 2017
Publicly Available Date	Jan 5, 2017
Journal	Frontiers in Genetics
Electronic ISSN	1664-8021
Publisher	Frontiers Media
Peer Reviewed	Peer Reviewed
Volume	7
Article Number	52
DOI	https://doi.org/10.3389/fgene.2016.00052
Keywords	impulsivity, binge drinking, adolescent, fMRI, BXD recombinant inbred strains, monetary incentive delay, 5-choice serial reaction time task
Public URL	https://nottingham-repository.worktribe.com/output/786081
Publisher URL	http://journal.frontiersin.org/article/10.3389/fgene.2016.00052/full
Contract Date	Jan 5, 2017