Methylation of the Glucocorticoid Receptor Gene Promoter in Preschoolers: Links With Internalizing Behavior Problems

Accumulating evidence suggests that early adversity is linked to methylation of the glucocorticoid receptor (GR) gene, NR3C1, which is a key regulator of the hypothalamic-pituitary-adrenal axis. Yet no prior work has considered the contribution of methylation of NR3C1 to emerging behavior problems and psychopathology in childhood. This study examined the links between methylation of NR3C1 and behavior problems in preschoolers. Data were drawn from a sample of preschoolers with early adversity (n=171). Children ranged in age from 3 to 5years, were racially and ethnically diverse, and nearly all qualified for public assistance. Seventy-one children had child welfare documentation of moderate to severe maltreatment in the past 6months. Structured record review and interviews in the home were used to assess early adversity. Parents reported on child internalizing and externalizing behavior problems. Methylation of NR3C1 at exons 1(D), 1(F), and 1(H) were measured via sodium bisulfite pyrosequencing from saliva DNA. Methylation of NR3C1 at exons 1(D) and 1(F) was positively associated with internalizing (r=.21, p<.01 and r=.23, p<.01, respectively), but not externalizing, behavior problems. Furthermore, NR3C1 methylation mediated effects of early adversity on internalizing behavior problems. These results suggest that methylation of NR3C1 contributes to psychopathology in young children, and NR3C1 methylation from saliva DNA is salient to behavioral outcomes.