Mouse and Human Genetic Analyses Associate Kalirin with Ventral Striatal Activation during Impulsivity and with Alcohol Misuse

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.

Associations between Polygenic Risk for Psychiatric Disorders and Substance Involvement

“…Fourth, while our PRS approach yielded evidence that shared common genetic architecture contributes to comorbidity between psychopathology and substance involvement, it does not provide insight into specific biological (e.g., reward-related neural responsiveness, epigenetically medicated changes in gene expression), psychological (e.g., anhedonia, impulsivity), and/or experiential (e.g., early life stress, peer group) mechanisms through which this risk is manifest (e.g., Olfson et al, 2014 ; Peña-Oliver et al, 2016 ; Ron and Barak, 2016 ). Compelling evidence suggests that psychopathology and substance involvement share overlapping neural systems (e.g., Buckholtz and Meyer-Lindenberg, 2012 ), molecular pathways (e.g., Ng et al, 2013 ), and environmental exposures (e.g., Kristjansson et al, 2016 ).…”

Heightened Impulsivity: Associated with Family History of Alcohol Misuse, and a Consequence of Alcohol Intake

“…Some forms of impulsivity have already been proposed as a behavioral endophenotype (produced reliable genetic associations; e.g., increased in siblings of drug abusers) mediating risk for other substance use disorders (stimulants), which may be exacerbated by chronic drug exposure (Ersche et al., ). Data indicating that impulsivity is highly heritable (e.g., VanderBroek et al., ) lend further support to the idea of impulsivity as an intermediate phenotype for AUD (Peña‐Oliver et al., ). However, the role of waiting impulsivity as a premorbid factor for alcohol abuse and its modification by acute alcohol in the absence of AUD remain unexplored.…”

Promising Pharmacogenetic Targets for Treating Alcohol Use Disorder: Evidence from Preclinical Models

“…A recent preclinical study examined expression patterns of cortical genes and impulsive behavior in BXD strains of mice [122]. PFC transcript levels of Kalrn, a gene encoding the Rho activating GTPase kalirin, significantly correlated with prema ture responding in BXDs tested on the 5choice serial reaction time task.…”

“…PFC transcript levels of Kalrn, a gene encoding the Rho activating GTPase kalirin, significantly correlated with prema ture responding in BXDs tested on the 5choice serial reaction time task. Of the human homologs of genes that correlated with premature responding in mice, SNPs in KALRN were associated with enhanced acti vation of the ventral striatum during anticipation of rewards and an increased frequency of binge drinking in adolescents [122]. The basolateral amygdala sends excitatory projections to the PFC, and a recent paper reported reduced KALRN expression in the baso lateral amygdala from human alcoholic postmortem tissue [111].…”