A KCNJ6 gene polymorphism modulates theta oscillations during reward processing

Abstract

Event related oscillations (EROs) are heritable measures of neurocognitive function that have served as useful phenotype in genetic research. A recent family genome-wide association study (GWAS) by the Collaborative Study on the Genetics of Alcoholism (COGA) found that theta EROs during visual target detection were associated at genome-wide levels with several single nucleotide polymorphisms (SNPs), including a synonymous SNP, rs702859, in the KCNJ6 gene that encodes GIRK2, a G-protein inward rectifying potassium channel that regulates excitability of neuronal networks. The present study examined the effect of the KCNJ6 SNP (rs702859), previously associated with theta ERO to targets in a visual oddball task, on theta EROs during reward processing in a monetary gambling task. The participants were 1601 adolescent and young adult offspring within the age-range of 17-25years (800 males and 801 females) from high-dense alcoholism families as well as control families of the COGA prospective study. Theta ERO power (3.5-7.5Hz, 200-500ms post-stimulus) was compared across genotype groups. ERO theta power at central and parietal regions increased as a function of the minor allele (A) dose in the genotype (AA>AG>GG) in both loss and gain conditions. These findings indicate that variations in the KCNJ6 SNP influence magnitude of theta oscillations at posterior loci during the evaluation of loss and gain, reflecting a genetic influence on neuronal circuits involved in reward-processing. Increased theta power as a function of minor allele dose suggests more efficient cognitive processing in those carrying the minor allele of the KCNJ6 SNPs. Future studies are needed to determine the implications of these genetic effects on posterior theta EROs as possible "protective" factors, or as indices of delays in brain maturation (i.e., lack of frontalization).

Keywords: Alcoholism; COGA; Event-related oscillations (EROs); GIRK2; KCNJ6; Monetary gambling task; Reward processing; Theta power.

Fig. 1

Schematic illustration of the monetary gambling task. Each trial starts with a choice stimulus (CS) which lasts for 800 ms and displays two amounts (10¢ or 50¢) to bet with. The participant selects one of the amounts and receives an outcome of either gain (green box) or loss (red box) for the selected amount as shown by the outcome stimulus (OS). A trial with a gain of 50¢ and the next trial with a loss of 10¢ are illustrated. The ISI between the CS and the OS is 1500 ms. Participants were required to respond to the OS within 1000 ms (i.e., response window) by selecting one of the two amounts. ERO analysis was performed on trial epochs of 1000 ms post-stimulus period after the onset of the OS (i.e., analysis window).

Fig. 2

Sixty-one electrodes were recorded in the current study from the surface of the scalp. Three regions, representing frontal (F3, FZ, F4), central (C3, CZ, C4), and parietal (P3, PZ, P4) electrodes were selected for statistical analyses (see shaded electrodes contributing to each of these regions).

Fig. 3

Theta-band response elicited by loss (A) and gain (B) feedback in the gambling task. Log-transformed theta power (estimated marginal means) is plotted as a function of scalp region and rs702859 genotype. Bonferroni adjusted multiple comparisons of log-transformed theta power (estimated marginal means) across genotypes [AA/0 = green line; AG/1 = blue line; GG/2 = red line] at frontal, central, and parietal regions during loss (left panel) and gain condition (right panels) in all subjects. Significant differences in theta power between the genotypes (0, 1, and 2) have been marked with corresponding genotype numbers and asterisks (*p < 0.05 and **p < 0.01). Additive effect of genotype [GG > AG > AA] is seen with significant differences observed between AA and GG [GG > AA] at central (*p < 0.05) and parietal (**p < 0.01) regions during both loss and gain condition, while the gain condition additionally showed a significant difference between AG and GG [GG > AA] at the parietal region (*p < 0.05). Step-wise increase in posterior theta power as a function of minor allele(s) is shown by the difference values between frontal and parietal regions (Frontal – Parietal) within each condition and genotype, positive values represent frontal maxima and negative values parietal maxima (**p < 0.01 and ***p < 0.001). The vertical error-bars in the line graph represents 1 standard error, shown only for positive or negative direction in order to avoid any overlap with the data lines.

Fig. 4

Theta power (in µV²) across genotypes (rs702859) during loss (panel-set A) and gain (panel-set B). Within these panel-sets, TF plots (middle panels showing x-axis with time in ms and y-axis with frequency in Hz for the loss and gain conditions at FZ and PZ electrodes) and head maps of absolute (left panels) and Z-scores (right panels) are illustrated. The dotted vertical line (at 0 ms) in the TF plots represents the onset of outcome stimulus. The smaller rectangles within the TF plots represent the TFROI of theta power (3.5–7.5 Hz within 200–500 ms) post outcome stimulus. During evaluation of loss as well as gain, there is an additive effect of genotypes [GG > AG > AA] with increasing power corresponding the number of minor allele(s) in central and parietal regions. Subtle topographic differences across genotypes (i.e., minor allele(s) contributing to posteriorization of theta power) are also shown.

Fig. A1

ERP waveforms (panels in columns 2, 3, and 4) flanked by P3 topography (panels in columns 1 and 5) across the genotypes (panels in rows) during loss and gain outcome. The group with minor allele(s) have displayed higher P3 amplitude than the group homozygous for the major allele [GG/AG > AA], prominently at the posterior region, during evaluation of loss as well as gain. Peak P3 amplitude values (in µV) for gain (green) and loss (red) are shown within the panels of ERP waveforms. The dotted vertical line (at 0 ms) in the waveform panels represents the onset of outcome stimulus. Uniform color scales have been used for all the head plots.

Fig. A2

Theta power (in µV²) across genotypes (rs702859) and age groups during loss (left columns) and gain condition (right columns). Additive effect of genotypes [GG > AG > AA] with increasing power corresponding the number of minor allele(s) in adolescent (17–18 years) and adult (19–25 years) groups is shown during evaluation of loss as well as gain. The adolescents show more theta power and more diffused posterior topography than adults in each genotype group (top three rows) and in the combined sample (bottom row of head maps). Uniform color scales have been used for all the head plots.