Association between the oxytocin receptor (OXTR) gene and mesolimbic responses to rewards

Abstract

Background: There has been significant progress in identifying genes that confer risk for autism spectrum disorders (ASDs). However, the heterogeneity of symptom presentation in ASDs impedes the detection of ASD risk genes. One approach to understanding genetic influences on ASD symptom expression is to evaluate relations between variants of ASD candidate genes and neural endophenotypes in unaffected samples. Allelic variations in the oxytocin receptor (OXTR) gene confer small but significant risk for ASDs for which the underlying mechanisms may involve associations between variability in oxytocin signaling pathways and neural response to rewards. The purpose of this preliminary study was to investigate the influence of allelic variability in the OXTR gene on neural responses to monetary rewards in healthy adults using functional magnetic resonance imaging (fMRI).

Methods: The moderating effects of three single nucleotide polymorphisms (SNPs) (rs1042778, rs2268493 and rs237887) of the OXTR gene on mesolimbic responses to rewards were evaluated using a monetary incentive delay fMRI task.

Results: T homozygotes of the rs2268493 SNP demonstrated relatively decreased activation in mesolimbic reward circuitry (including the nucleus accumbens, amygdala, insula, thalamus and prefrontal cortical regions) during the anticipation of rewards but not during the outcome phase of the task. Allelic variation of the rs1042778 and rs237887 SNPs did not moderate mesolimbic activation during either reward anticipation or outcomes.

Conclusions: This preliminary study suggests that the OXTR SNP rs2268493, which has been previously identified as an ASD risk gene, moderates mesolimbic responses during reward anticipation. Given previous findings of decreased mesolimbic activation during reward anticipation in ASD, the present results suggest that OXTR may confer ASD risk via influences on the neural systems that support reward anticipation.

Figure 1

Response times (in ms) during incentive trials of the monetary incentive delay (MID) task for different oxytocin receptor (OXTR) gene single nucleotide polymorphisms (SNPs) grouped based on rs2268493, rs237887 and rs1042778 allelic variants. OXTR, oxytocin receptor; SNP, single nucleotide polymorphism.

Figure 2

Brain regions showing significant activation for incentive versus non-incentive trials during the anticipation phase of the monetary incentive delay task across the entire sample.Z values indicate cluster thresholds. ACG, anterior cingulate gyrus; L, left; NAcc, nucleus accumbens.

Figure 3

Brain regions showing significantly reduced activation for the OXTR SNP rs2268493 risk allele group during the anticipation phase of the monetary incentive delay task using both a general linear model approach and permutation testing. (a) General linear model analyses (in red). Z values indicate cluster thresholds. (b) Randomize permutation testing analysis (in blue). Note the convergence of effects in the left NAcc and ACG. ACG, anterior cingulate gyrus; L, left; NAcc, nucleus accumbens; OXTR, oxytocin receptor; PCG, paracingulate gyrus; SNP, single nucleotide polymorphism.

Figure 4

Brain regions showing significantly reduced activation for the OXTR SNP rs237887 risk allele group the during the anticipation phase of the monetary incentive delay task. Z values indicate cluster thresholds. L, left; MFG, middle frontal gyrus; OXTR, oxytocin receptor; SNP, single nucleotide polymorphism.