Indeed, recent studies that aimed to decipher the biological mechanisms involved in the development and maintenance of chronic aggression have consistently found a key role for the serotonin pathway, suggesting lower serotoninergic activity associated with FDA-approved Compound Library aggression/impulsivity. Tryptophan Hydroxylase is the rate-limiting enzyme in the synthesis of serotonin. In humans, Perez-Rodriguez et al. tested several polymorphisms of TPH2 and found an extended haplotype associated with enhanced aggressiveness, suicidal behavior, and susceptibility to borderline personality disorder. The glucocorticoid receptor, whose epigenetic changes, were associated with early-life stress, plays also a key role in HPA axis related stress reactivity and aggressive behavior in pigs. The stress response and the HPA axis have also been associated with aggression. Both hyper- and hypo-active HPA axis are associated with aggression in humans. It is perhaps not surprising that these genes are differentially methylated only in women where the HPA negative feedback control is known to be more sensitive than in males. The same is true for rodents where it has been shown that female rodents have higher HPA axis activity under basal and stressinduced conditions than males. As previously observed in men, several of the genes in the female aggression signature play roles in cytokine function and inflammatory response. Recent studies have shown that cytokines are associated with various behavioral disorders such as anxiety, depression, suicide, FG-4592 childhood mood disorder and post-traumatic stress disorder. It was also suggested that cytokines might play a role in the neurobiology of aggression since they are expressed in brain regions already known to be involved in aggression and behavior. Our results show that IL1RN belongs to both the male and female aggression signatures. Moreover, cytokines expression in blood and gene methylation in T cells was recently found to associate with men CPA in the same subjects as the one studied here. Further work is needed to investigate the role of peripheral cytokines in aggression but taken together these data suggest that cytokine regulation could play an important role in human behavior and mental health. It is noteworthy that although these genes are clearly involved in brain function, we also observed changes in DNA methylation in T cells associated with aggressive behavior. Similar results were obtained when we recently compared rhesus monkey DNA methylation changes in prefrontal cortex and T cells in response to differences in maternal rearing. This analysis revealed both tissue specific alterations as well as common differentially methylated regions in T cells and prefrontal cortex. Two previous reports suggested that brain function-specific genes were differentially methylated in peripheral blood cells in association with physical aggression. Further work is needed to understand why seemingly brain-specific genes would be differentially methylated in blood DNA in association with aggression and other environmental factors. There are three important limitations to this study. First, although we recruited subjects from a large longitudinal study, we managed to assess only a small number of women with chronic physical aggression because they represent a very small percentage of the population and are difficult to recruit. Thus, replications are needed from similar longitudinal studies to confirm our results.