Mouse and Human Genetic Analyses Associate Kalirin with Ventral Striatal Activation during Impulsivity and with Alcohol Misuse.
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.
School of Psychology, University of SussexBrighton, UK; Department of Psychology, University of CambridgeCambridge, UK.
Yolanda
Y
Peña-Oliver
Institute of Psychiatry, Psychology and Neurosciences, Kings CollegeLondon, UK; MRC Social, Genetic and Developmental Psychiatry CentreLondon, UK.
Fabiana M
FM
Carvalho
School of Psychology, University of Sussex Brighton, UK.
Sandra
S
Sanchez-Roige
Institute of Psychiatry, Psychology and Neurosciences, Kings CollegeLondon, UK; MRC Social, Genetic and Developmental Psychiatry CentreLondon, UK.
Erin B
EB
Quinlan
Institute of Psychiatry, Psychology and Neurosciences, Kings CollegeLondon, UK; MRC Social, Genetic and Developmental Psychiatry CentreLondon, UK.
Tianye
T
Jia
Institute of Psychiatry, Psychology and Neurosciences, Kings CollegeLondon, UK; MRC Social, Genetic and Developmental Psychiatry CentreLondon, UK.
Tom
T
Walker-Tilley
Genome Damage and Stability Centre, University of Sussex Brighton, UK.
Stuart L
SL
Rulten
School of Life Sciences, University of Sussex Brighton, UK.
Frances M G
FM
Pearl
Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University Mannheim, Germany.
Tobias
T
Banaschewski
Institute of Psychiatry, Psychology and Neurosciences, Kings College London, UK.
Gareth J
GJ
Barker
Institute of Neuroscience, Trinity College Dublin Dublin, Ireland.
Arun L W
AL
Bokde
Universitätsklinikum Hamburg Eppendorf Hamburg, Germany.
Christian
C
Büchel
Institute of Psychiatry, Psychology and Neurosciences, Kings CollegeLondon, UK; MRC Social, Genetic and Developmental Psychiatry CentreLondon, UK.
Patricia J
PJ
Conrod
Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University Mannheim, Germany.
Herta
H
Flor
Universitätsklinikum Hamburg Eppendorf Hamburg, Germany.
Jürgen
J
Gallinat
Institute of Neuroscience, Trinity College DublinDublin, Ireland; Departments of Psychiatry and Psychology, University of VermontBurlington, VT, USA.
Hugh
H
Garavan
Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Charité-Universitätsmedizin Berlin, Germany.
Andreas
A
Heinz
School of Psychology, University of Nottingham Nottingham, UK.
Penny
P
Gowland
INSERM, UMR 1000, Research Unit Imaging and Psychiatry, IFR49, CEA, DSV, I2BM-Service Hospitalier Frédéric Joliot Orsay, France.
Marie-Laure
ML
Paillere Martinot
Rotman Research Institute, University of TorontoToronto, ON, Canada; Department of Psychology and Psychiatry, University of TorontoToronto, ON, Canada.
Tomáš
T
Paus
Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University Mannheim, Germany.
Marcella
M
Rietschel
Department of Psychology, University of Cambridge Cambridge, UK.
Trevor W
TW
Robbins
Department of Psychiatry and Psychotherapy, Technische Universität Dresden Dresden, Germany.
Michael N
MN
Smolka
Institute of Psychiatry, Psychology and Neurosciences, Kings CollegeLondon, UK; MRC Social, Genetic and Developmental Psychiatry CentreLondon, UK.
Gunter
G
Schumann
School of Psychology, University of Sussex Brighton, UK.
David N
DN
Stephens
5-choice serial reaction time task; BXD recombinant inbred strains; adolescent; binge drinking; fMRI; impulsivity; monetary incentive delay