Several methodological considerations arise in our study. First, with blood available only in adulthood, we cannot establish when during development chronic physical aggression became associated with these particular DNA methylation alterations and cytokine level reduction in plasma. Based on the longitudinal data obtained from this cohort, we can expect that DNA methylation changes appear early in life as chronic physical aggression trajectories usually start in infancy and are associated with numerous factors during the prenatal and early postnatal periods [5]. However, it stands to reason that there is a developmental trajectory of these DNA methylation changes and that changes seen in adults will not be identical to the early changes seen in aggressive children. The second issue relates to cause and effect. We have demonstrated here a highly significant association between DNA methylation alterations and CPA. These changes could be either a cause or an effect of CPA life style. The issue of causality is particularly difficult in human studies although a parallel longitudinal analysis of behavioral and DNA methylation changes could have established at least the temporal relationship between
