Behavioral problems in childhood are oftenthe earliest and most reliable predictors of developing a psychiatric disorder(Roza et al., 2003). Internalizing problems are associated with both mood andanxiety disorders, which share high-comorbidity rates and a common dysregulatedhypothalamic-pituitary-adrenal (HPA) axis endophenotype (Tandon et al., 2009).A large body of research suggests early adverse experiences may shape mentalhealth related physiology and behavior through altering methylation of the NR3C1gene (Palma-Gudiel et al., 2015). The NR3C1 gene codes for theglucocorticoid receptor, a central component in HPA axis regulation. However,much of this research did not control for genetic influences on methylationlevels. Therefore we used a monozygotic (MZ) twin design to control forgenetic effects. First, we used mixed-model regression analyses to investigatethe hypothesis that NR3C1 methylation is associated with internalizingbehavior. Next, we used linear regression to test the hypothesis that MZdifferences in internalizing is associated with MZ difference in genemethylation. Our sample included 96 monozygotic twins (48 families; 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). We collected buccal cell samples and conductedprimary caregiver interviews to assess internalizing symptoms (MacArthur Healthand Behavioral Questionnaire [HBQ]) during home visits. DNA methylation wasquantified using the Infinium MethylationEPIC BeadChip. We included 33 CpGswithin NR3C1 promoter regions to extract the first principal componentafter removing all sites with a < .3 loading (18 CpG sites remained;variance explained 35.17%, all sites loaded from .31 - .81). Results indicated NR3C1methylation was a significant predictor of internalizing symptoms (b =-0.056, p = 0.012), however MZ differences in internalizing were notsignificantly related to MZ differences in methylation. These resultssuggest that dynamic methylation of the NR3C1 gene may be anendophenotype related to internalizing behavior. However, this association maybe genetically driven more than environmentally driven. These results implicateDNA methylation as a possible molecular marker related to children’s mentalhealth and risk for psychiatric disorders.
Lemery-Chalfant, K., Clifford, S., McDonald,K., O'Brien, T. C., & Valiente, C. (2013). Arizona Twin Project: A focus onearly resilience. Twin Research and Human Genetics, 16(1),404-411.
Palma-Gudiel, H., Córdova-Palomera, A., Leza,J. C., & Fananás, L. (2015). Glucocorticoid receptor gene (NR3C1)methylation processes as mediators of early adversity in stress-relateddisorders causality: a critical review. Neuroscience & BiobehavioralReviews, 55, 520-535.
Tandon, M., Cardeli, E., & Luby, J.(2009). Internalizing disorders in early childhood: A review of depressive andanxiety disorders. Child and Adolescent Psychiatric Clinics, 18(3),593-610.
Roza, S. J., Hofstra, M. B., van der Ende,J., & Verhulst, F. C. (2003). Stable prediction of mood and anxietydisorders based on behavioral and emotional problems in childhood: A 14-yearfollow-up during childhood, adolescence, and young adulthood. AmericanJournal of Psychiatry, 160(12), 2116-2121.
Psychopathology (e.g., Internalizing, Externalizing, Psychosis) , other
