Dissociable Genetic Contributions to Error Processing: A Multimodal Neuroimaging Study

Abstract

BackgroundNeuroimaging studies reliably identify two markers of error commission: the error-related negativity (ERN), an event-related potential, and functional MRI activation of the dorsal anterior cingulate cortex (dACC). While theorized to reflect the same neural process, recent evidence suggests that the ERN arises from the posterior cingulate cortex not the dACC. Here, we tested the hypothesis that these two error markers also have different genetic mediation.MethodsWe measured both error markers in a sample of 92 comprised of healthy individuals and those with diagnoses of schizophrenia, obsessive-compulsive disorder or autism spectrum disorder. Participants performed the same task during functional MRI and simultaneously acquired magnetoencephalography and electroencephalography. We examined the mediation of the error markers by two single nucleotide polymorphisms: dopamine D4 receptor (DRD4) C-521T (rs1800955), which has been associated with the ERN and methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133), which has been associated with error-related dACC activation. We then compared the effects of each polymorphism on the two error markers modeled as a bivariate response.ResultsWe replicated our previous report of a posterior cingulate source of the ERN in healthy participants in the schizophrenia and obsessive-compulsive disorder groups. The effect of genotype on error markers did not differ significantly by diagnostic group. DRD4 C-521T allele load had a significant linear effect on ERN amplitude, but not on dACC activation, and this difference was significant. MTHFR C677T allele load had a significant linear effect on dACC activation but not ERN amplitude, but the difference in effects on the two error markers was not significant.Conclusions DRD4 C-521T, but not MTHFR C677T, had a significant differential effect on two canonical error markers. Together with the anatomical dissociation between the ERN and error-related dACC activation, these findings suggest that these error markers have different neural and genetic mediation.

Effects of an opioid (proenkephalin) polymorphism on neural response to errors in health and cocaine use disorder

“…To our knowledge, this is one of the first studies to examine the functional correlates of this gene in human SUD – and the first to use functional neuroimaging for this purpose. This research augments work aiming to clarify the mechanisms underlying opioid genes’ modulation of addictive disorders in humans [25, 26, 93] and of error-related processing more generally [94]. More importantly, our results suggest an intermediate phenotype that can increase understanding of the PENK gene’s contribution to disease-relevant phenotypes such as SUD [41].…”

The genetics of anxiety‐related negative valence system traits

“…As reviewed by Manoach and Agam [], several genes from the dopaminergic system have been associated with ERN or the related deltaERN measure (difference between the ERN and CRN), with an association of the DAT1 VNTR and conflicting evidence across studies for association of DRD2 , DRD4 , and COMT . The DRD4 variant rs1800955 (T allele) was associated with increased ERN in one study included in the review [Kramer et al, ], but a more recent study reported an opposite direction of effect [Agam et al, ]. An additional study of the COMT Val158Met polymorphism supported the association of the Val allele with increased ERN, an effect that was moderated by the acute administration of dopamine [Mueller et al, ].…”

Endophenotype best practices

“…To date, there has only been one replicated finding. Two studies have reported associations between ERN amplitude and a polymorphism of the DRD4 receptor gene (Agam et al, 2014; Kramer et al, 2007). However, whereas this SNP accounted for approximately 13% of the variance in ERN amplitude in the initial study of Kramer et al, it only accounted for about 3% of variance in the subsequent study of Agam and colleagues (the “winner's curse”; Ioannidis, 2008), and this latter effect was statistically significant only because a one-tailed test was used.…”