Dopaminergic gene methylation is associated with cognitive performance in a childhood monozygotic twin study

Abstract

Individual differences in cognitive function are due to a combination of heritable and non-heritable factors. A large body of evidence from clinical, cognitive, and pharmacological neuroscience implicates dopaminergic gene variants as modulators of cognitive functions. Neuroepigenetic studies demonstrate environmental factors also influence complex phenotypes by affecting gene expression regulation. To evaluate the mechanism of environmental influence on cognitive abilities, we examined if epigenetic regulation of dopaminergic genes plays a role in cognition. Using a DNA methylation profiling microarray, we used a monozygotic (MZ) twin difference design to evaluate if co-twin differences in methylation of CpG sites near six dopaminergic genes predicted differences in response inhibition and memory performance. Studying MZ twins allows us to assess if environmentally driven differences in methylation affect differences in phenotype while controlling for the influence of genotype and shared family environment. Response inhibition was assessed with the flanker task and short-term and working memory were assessed with digit span recall. We found MZ co-twin differences in DRD4 gene methylation predicted differences in short-term memory. MZ differences in COMT, DBH, DAT1, DRD1, and DRD2 gene methylation predicted differences in response inhibition. 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. ARTICLE HISTORYORCID Candace R. Lewis http://orcid.org/0000-0001-5253-9989 Reagan S. Breitenstein http://orcid.org/0000-0001-9998-166X

Neural substrates of early executive function development

“…A recent study by Lewis et al (2019) examined the role of non-shared environmental experiences on methylation of dopaminergic genes, and the related association with cognitive task performance, in a cohort of 8 year old identical twins, thus controlling for genetic and early familial influences. They found that twin differences in DNA methylation levels of five dopaminergic genes (including COMT) predicted differences in EF.…”

Genetic Mechanisms of Cognitive Development

“…Between twins, differences in DRD4 gene methylation related to differentiation in short-term memory capacity were revealed, while differences in methylation of the DRD1, DRD2, COMT, DBH, and DAT1 genes caused individual differences in inhibition of cognitive reactions. The data obtained point to a significant impact of epigenomic modifications in the mainte-nance of complex cognitive characteristics and to a dissociative effect of methylation of dopaminergic genes in some of them [60].…”

“…In addition, changes in chromatin modifications as a response to learning were reported to be caused by acetylation, phosphorylation, and methylation of histones [59]. In order to estimate the mechanism of environmental impact on cognitive functioning, in 2019, Lewis et al [60] conducted an analysis of the role of epigenetic regulation of dopaminergic system genes in variation of cognitive abilities. The use of a microarray to detect the methylation profile of CpG sites neighboring six dopaminergic system genes helped to analyze differences in response inhibition and memory performance in monozygotic twins.…”

First-in-Human Randomized Trial to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the KDM1A Inhibitor Vafidemstat

“…The etiology of sporadic neurodegenerative disorders such as Alzheimer's or Parkinson's disease is currently unknown. Epigenetics plays an important role in brain development and the establishment and loss of memory and cognition [1][2][3][4]; modulation of epigenetic factors may present a unique opportunity for treatment of central nervous system (CNS) diseases [5].…”