Harsh Parenting Predicts Novel HPA Receptor Gene Methylation and NR3C1 Methylation Predicts Cortisol Daily Slope in Middle Childhood.

Adverse experiences in childhood are associated with altered hypothalamic-pituitary-adrenal (HPA) axis function and negative health outcomes throughout life. It is now commonly accepted that abuse and neglect can alter epigenetic regulation of HPA genes. Accumulated evidence suggests harsh parenting practices such as spanking are also strong predictors of negative health outcomes. We predicted harsh parenting at 2.5 years old would predict HPA gene DNA methylation similarly to abuse and neglect, and cortisol output at 8.5 years old. Saliva samples were collected three times a day across 3 days to estimate cortisol diurnal slopes. Methylation was quantified using the Illumina Infinium MethylationEPIC array BeadChip (850 K) with DNA collected from buccal cells. We used principal components analysis to compute a summary statistic for CpG sites across candidate genes. The first and second components were used as outcome variables in mixed linear regression analyses with harsh parenting as a predictor variable. We found harsh parenting significantly predicted methylation of several HPA axis genes, including novel gene associations with AVPRB1, CRHR1, CRHR2, and MC2R (FDR corrected p < 0.05). Further, we found NR3C1 methylation predicted a steeper diurnal cortisol slope. Our results extend the current literature by demonstrating harsh parenting may influence DNA methylation similarly to more extreme early life experiences such as abuse and neglect. Further, we show NR3C1 methylation is associated with diurnal HPA function. Elucidating the molecular consequences of harsh parenting on health can inform best parenting practices and provide potential treatment targets for common complex disorders.

Epigenetic differences in inflammation genes of monozygotic twins are related to parent-child emotional availability and health.

The inflammatory response is an immune defense engaged immediately after injury or infection. Chronic inflammation can be deleterious for various health outcomes and is characterized by high levels of pro-inflammatory markers such as C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α). A large body of research demonstrates these inflammatory markers are responsive to stress and quality of social relationships throughout the lifespan. For example, the quality of the early parental bond predicts various health outcomes and may be driven by changes in immune function. Epigenetic processes, such as DNA methylation, may be one mechanism by which early social experiences shape immune functioning. The present study used a monozygotic twin difference design to assess if mother-reported emotional availability at 1 year and 2.5 years predicted immune gene methylation at 8 years of age. Further, we assessed if inflammation gene methylation was related to general health problems (e.g. infections, allergies, etc.). We found that mother-reported emotional availability at 1 year, but not 2.5 years, was related to methylation of various immune genes in monozygotic twins. Furthermore, twin pairs discordant in health problems have more difference in immune gene methylation compared to twin pairs concordant for health problems, suggesting that methylation of immune genes may have functional consequences for general health. These results suggest that the emotional component of attachment quality during infancy contributes to immune epigenetic profiles in childhood, which may influence general health.

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

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.