Associations Between Dopaminergic Gene Methylation and Executive Performance in a Childhood MZ Twin Difference Design

Specific allele types of dopaminergic genes have been associated with cognitive function. However, an emerging body of empirical research suggests that environmental factors are also influencing complex phenotypes by affecting... [ view full abstract ]

Specific allele types of dopaminergic genes have been associated with cognitive function. However, an emerging body of empirical research suggests that environmental factors are also influencing complex phenotypes by affecting the epigenome. We used a monozygotic (MZ) twin difference design to assess if between-twin differences in methylation of CpG sites near dopaminergic genes predicted differences in cognitive performance of 48 MZ twin pairs (51% male; 50% Non-Hispanic White, 14.6% Hispanic/Latinx, 8.3% African American, 4.2% Asian American), mean age = 8.5 years, drawn from the Arizona Twin Project (Lemery-Chalfant et al., 2013). Comparing MZ twins allowed us to assess if environmentally driven differences in methylation affected phenotypes while controlling for the influence of genotype on methylation status. We collected buccal cell samples and conducted cognitive and memory tasks during home visits. DNA methylation was quantified using the Infinium MethylationEPIC BeadChip. Executive attention was assessed with the Flanker Task (Linear Integration Speed Accuracy Score [LISAS] for congruent and incongruent trials). Short-term and working memory were assessed with Digit Span (Total Forward [TF] and Backward [TB]). Since the number of CpGs near each gene ranged from 20-41, we used PCA to extract the first component after removing all sites with a < .3 loading (variance explained ranged from 45.12 - 70.15%). Next, we computed MZ difference scores from components and task performance for linear regression analysis controlling for sex. We found MZ co-twin differences in DRD4 (b = 0.359, p = 0.019) and DBH (b = 0.298, p = 0.045) methylation predicted differences in short-term memory. MZ differences in DBH (b = 0.311, p = 0.046) and trending for COMT (b = 0.277, p = 0.076) predicted differences in response inhibition. Lastly, differences in DAT1 trended towards predicting differences in executive attention (b = 0.284, p = 0.073). Taken together, findings suggest methylation status of dopaminergic genes may influence cognitive functions in a dissociable manner. Our results highlight the importance of the epigenome and environment, over and above the influence of genotype, in supporting complex cognitive functions.

Lemery-Chalfant, K., Clifford, S., McDonald, K., O'Brien, T. C., & Valiente, C. (2013). Arizona Twin Project: A focus on early resilience. Twin Research and Human Genetics, 16(1), 404-411.