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. 2016 Apr 7;7:52.
doi: 10.3389/fgene.2016.00052. eCollection 2016.

Mouse and Human Genetic Analyses Associate Kalirin With Ventral Striatal Activation During Impulsivity and With Alcohol Misuse

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Free PMC article

Mouse and Human Genetic Analyses Associate Kalirin With Ventral Striatal Activation During Impulsivity and With Alcohol Misuse

Yolanda Peña-Oliver et al. Front Genet. .
Free PMC article

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.

Keywords: 5-choice serial reaction time task; BXD recombinant inbred strains; adolescent; binge drinking; fMRI; impulsivity; monetary incentive delay.

Figures

Figure 1
Figure 1
Performance of C57BL/6J (C57, black bars), DBA/2J (DBA, clear bars) and the 10 BXD recombinant inbred strains (gray bars) in the 5-CSRTT for the baseline (mean of the last three sessions on stage 6) and the long ITI session. The values represent the mean ± SE Δp < 0.05, significantly different from C57, + p < 0.05 significantly different from DBA, *p < 0.05 vs. the strain with the highest value in the same session.
Figure 2
Figure 2
Group whole-brain positive BOLD map (n = 1423) for the contrast Anticipation big win vs. Baseline (FWE P < 0.05) with overlay of the two combined ROIs—ventral striatum (VS; top panel) and anterior cingulate cortex (ACC; bottom panel). The color bar indicates resulting statistical map z-scores.
Figure 3
Figure 3
Measures (Mean ± S.E.) associated with KALRN SNP variations. (A) Percentage of premature responses during “big win” trials in individuals carrying A or G alleles of KALRN SNP rs6438839 (n: AA = 9, AG = 204, GG = 1180); (B) Binge Drinking Score [coded in a 6-point scale ranging from 0 (“never”) to 5 (“10 times or more”)] in individuals carrying A or C alleles of KALRN SNP rs634050 (n: AA = 55, AC = 412, CC = 956); (C) Activation of Right Ventral Striatum during anticipation of a “big win” in individuals carrying A or G alleles of KALRN SNP rs6438839 (n: AA = 10, AG = 208, GG = 1205); (D) Activation of Left Ventral Striatum during anticipation of a “big win” in individuals carrying A or G alleles of KALRN SNP rs6438839 (n: AA = 10, AG = 208, GG = 1205).
Figure 4
Figure 4
(A) The LD plots of KALRN gene surrounding the SNPs of interest. The haplotype blocks are established through the four gamete test where the 4th gamete frequency is set to be higher than 0.05. SNPs of interest, i.e., rs4634050 and rs6438839, are contained in the same haplotype block. (B) The illustration of SNP locations on KALRN gene. The flanking SNPs of haplotype block defined in panel (A), i.e., rs4289301 and rs6438839, were highlighted in red and blue, respectively, where the later one is also one of the two target SNPs. The other target SNP, i.e., rs4634050, was also highlighted in green.

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