Functional Genetic Variation in Dopamine Signaling Moderates Prefrontal Cortical Activity During Risky Decision Making

Abstract

Brain imaging has revealed links between prefrontal activity during risky decision-making and striatal dopamine receptors. Specifically, striatal dopamine D2-like receptor availability is correlated with risk-taking behavior and sensitivity of prefrontal activation to risk in the Balloon Analogue Risk Task (BART). The extent to which these associations, involving a single neurochemical measure, reflect more general effects of dopaminergic functioning on risky decision making, however, is unknown. Here, 65 healthy participants provided genotypes and performed the BART during functional magnetic resonance imaging. For each participant, dopamine function was assessed using a gene composite score combining known functional variation across five genes involved in dopaminergic signaling: DRD2, DRD3, DRD4, DAT1, and COMT. The gene composite score was negatively related to dorsolateral prefrontal cortical function during risky decision making, and nonlinearly related to earnings on the task. Iterative permutations of all possible allelic variations (7777 allelic combinations) was tested on brain function in an independently defined region of the prefrontal cortex and confirmed empirical validity of the composite score, which yielded stronger association than 95% of all other possible combinations. The gene composite score also accounted for a greater proportion of variability in neural and behavioral measures than the independent effects of each gene variant, indicating that the combined effects of functional dopamine pathway genes can provide a robust assessment, presumably reflecting the cumulative and potentially interactive effects on brain function. Our findings support the view that the links between dopaminergic signaling, prefrontal function, and decision making vary as a function of dopamine signaling capacity.

Figure 1

Nonlinear relationship between dopamine gene scores and earnings on the BART. Scatter plot depicts a quadratic relationship between dopamine gene scores and earnings on the BART. Values for earnings and dopamine composite gene scores were adjusted for age and sex.

Figure 2

Negative relationship between dopamine gene scores and the parametric modulation of activation by pump number during risky decision making. Significant relationships were observed involving the right and left middle frontal gyrus, right parietal cortex, and posterior cingulate cortex (p<0.05, whole-brain cluster corrected, controlling for age and sex (n=65)). Statistical significance was retained, with the exception of the posterior cingulate cortex after excluding all but the Caucasian and Hispanic participants (n=42) and after controlling for ethnicity (n=65).

Figure 3

Effect size maps for the relationship between brain function during risky decision-making and dopamine gene score and each gene. For each gene, maps of effect sizes (Cohen's D) show the contribution of each gene to the parametric modulation of brain activation by risk during risky decision making. Outlined in yellow is the cluster in the right dorsolateral prefrontal cortex that showed a significant relationship with the dopamine gene score in the whole-brain analysis.