Variation on the dopamine D2 receptor gene (DRD2) is associated with basal ganglia-to-frontal structural connectivity

Abstract Dopaminergic neurotransmission in the mesocortical system is crucial for higher order cognition. Common variation on the dopamine D2 receptor (DRD2) gene has been linked to individual differences in dopaminergic signaling and was also repeatedly associated to cognitive markers. The relationship between dopaminergic genetic variants and neurostructural properties of the mesocortical system, however, has received little attention so far. Recently, the direction of a dopaminergic manipulation was predicted from the integrity of fiber tracts between subcortical areas and the frontal lobes. Fiber tract integrity was therefore proposed as an indicator of baseline dopamine activity. This raises the question whether DRD2 variants that relate to dopamine turnaround are also linked to fiber tract integrity. In the present study we assessed associations between the DRD2 rs6277 polymorphism and subcortical connections from connectome maps derived from diffusion weighted imaging in n=105 healthy volunteers (43 males and 62 females). Carriers of the CC genotype who are characterized by elevated striatal dopamine turnaround showed higher integrity in terms of fractional anisotropy on fiber tracts between the basal ganglia and frontal regions compared to carriers of the CT and TT variant. Our results indicate that structural connectivity could serve as a conceptual link between genetically determined individual differences in dopaminergic activity and effects of dopamine challenges on executive functioning.