Association of mineralocorticoid receptor gene (NR3C2) hypermethylation in adult males with aggressive behavior

Abstract Aggressive behavior may have adaptive value under some environmental conditions. However, when it is extreme or improper, it may also lead to maladaptive results, seriously threatening human and social well-being. Aggressive behavior is a multifactorial disease, and the etiology is largely unknown. The stress-related hypothalamic-pituitary-adrenal (HPA) axis is a crucial system in the stress response that has emerged as a potential mechanism of aggressive behavior. The NR3C2 gene is an important regulator of the HPA axis: it is involved in regulating HPA axis activity and behavioral adaptation to stressors. Moreover, the epigenetic mechanism of DNA methylation has been suggested to mediate the development of aggressive behavior. However, the association between NR3C2 methylation and aggressive behavior has not been studied. In the present study, we assessed NR3C2 methylation (including three regions: promoter P1, exon 1α, and the sequence downstream of exon 1α) in peripheral blood DNA of adult males with aggressive behavior (n = 106) and healthy controls (n = 104). We found the NR3C2 gene to be associated with aggressive behavior, with hypermethylation detected in the entire aggressive behavior group as well as in the robbery subgroup compared to controls. In addition, analysis of methylation at 75 CpG sites revealed that some important CpG sites are associated with aggressive behavior. Our results suggest that HPA axis-related gene NR3C2 methylation is associated with aggressive behavior. These results lend support for using NR3C2 DNA methylation as a potential biomarker of aggressive behavior.