Multilocus genetic composite reflecting dopamine signaling capacity predicts reward circuitry responsivity

Abstract

The objective of the study was to test the hypotheses that humans with genotypes putatively associated with low dopamine (DA) signaling capacity, including the TaqIA A1 allele, DRD2-141C Ins/Ins genotype, DRD4 7-repeat or longer allele, DAT1 10-repeat allele, and the Met/Met COMT genotype, and with a greater number of these genotypes per a multilocus composite, show less responsivity of reward regions that primarily rely on DA signaling. Functional magnetic resonance imaging (fMRI) paradigms were used to investigate activation in response to receipt and anticipated receipt of palatable food and monetary reward. DNA was extracted from saliva using standard methods. Participants were 160 adolescents (mean age = 15.3 years, SD = 1.07 years; mean body mass index = 20.8, SD = 1.9). The main outcome was blood oxygenation level-dependent activation in the fMRI paradigms. Data confirmed that these fMRI paradigms activated reward, attention, somatosensory, and gustatory regions. Individuals with, versus without, these five genotypes did not show less activation of DA-based reward regions, but those with the Met/Met versus the Val/Val COMT genotype showed less middle temporal gyrus activation and those with the DRD4-L versus the DRD4-S genotype showed less middle occipital gyrus activation in response to monetary reward. Critically, the multilocus composite score revealed that those with a greater number of these genotypes showed less activation in reward regions, including the putamen, caudate, and insula, in response to monetary reward. The results suggest that the multilocus genetic composite is a more sensitive index of vulnerability for low reward region responsivity than individual genotypes.

Figure 1.

A–D, Main effects in the right putamen (MNI coordinates: 27, 11, −11, Z = 3.81, k = 19), in response to milkshake cue–tasteless solution cue (A), bilateral postcentral gyrus (MNI coordinates: −42, −19, 37, Z = Inf, k = 14966; extending into frontal operculum, insula, striatum, and midbrain) in response to milkshake receipt–tasteless solution receipt (B), bilateral orbitofrontal cortex (MNI coordinates: 33, 17, −17, Z = 6.50, k = 213; −33, 17, −14, Z = 6.35, k = 150) in response to potential win-neutral coin display (C), and midbrain (MNI coordinates: 0, −28, −5, Z = 3.62, k = 15) in response to win-neutral coin display (D).

Figure 2.

Greater activation in the midbrain (MNI coordinates: 12, −25, −23, Z = 4.49, k = 49) in A1 carriers versus A2 homozygotes in response to milkshake cue–tasteless solution cue with the bar graphs of parameter estimates from the peak.

Figure 3.

Correlation between the multilocus genetic composite and activation in the left putamen (MNI coordinates: −30, −19, 10, Z = 3.32, k = 19) plus a coronal image of activation in the caudate (MNI coordinates: 21, 2, 19, Z = 3.62, k = 20) in response to win-neutral coin display.