We studied a mixed population of psychiatric outpatients and healthy volunteers in order to examine the gene-environment interaction effect of MAOA genotype and early trauma on the increased risk for self-reported levels of physical aggression during adulthood. We found that levels of physical aggression were significantly higher in men who had experienced traumatic events during the first 15 years of life and who carried the low expression allele (MAOA-L). When we repeated the analysis in the sub-sample of healthy volunteers, the results did not change. Our results are consistent with the majority of previous reports 
and point toward the MAOA genotype as a genetic factor that moderates the impact of early traumatic life events on the developmental pathway leading to later-life aggression.
Based on the findings of several independent studies, the relationship between the MAOA polymorphism and aggression appears to be fairly consistent. Yet, the intervening neural and psychological mechanisms are still unclear. One promising line of research has investigated the possibility that individuals with the low expression allele might be more sensitive to negative social experiences, which might ultimately result in defensively aggressive behavior. A recent fMRI study showed that the MAOA genotype at risk for impulsivity and violent behavior is associated with reduced gray matter volumes in limbic regions such as the amygdala, dorsal anterior cingulated cortex (dACC), and subgenual ACC and greater amygdala and subgenual ACC responsivity to negative emotional faces 
. Consistent with the social hypersensitivity hypothesis, Eisenberger et al. (2007) have found that, compared to individuals with the high expression allele, healthy men and women with the MAOA-L reported higher trait aggression, higher interpersonal sensitivity and showed greater dorsal anterior cingulated cortex activity (associated with rejection-related distress) in response to social exclusion 
. If replicated by future studies, these preliminary findings suggest that the MAOA-L would confer a vulnerability to negative social experiences, including early trauma, and a specific proclivity toward reactive aggression, i.e. that type of aggression triggered by exaggerated levels of negative emotion, such as anger and anxiety.
Although recent research has demonstrated that the allele×environment strategy is promising for detecting individual vulnerability to environmental risk, reported associations between gene variants and complex behaviors are in general weak. This is likely to reflect the fact that a number of several alleles contribute in various small ways to the interplay between environmental risk factors and development of complex behaviors. In the case of G×E interactions involving MAOA alleles and predicting antisocial behavior and/or conduct disorder, effect sizes reported to date are small on average. In this regard, the present study is no exception. The cumulative variance in the physical aggression score explained by the ANOVA effects involving the MAOA allele was 6.6% in the entire sample and 12.1% in the sub-sample of healthy volunteers. However, the significant G×E interaction effects found in the present study are remarkable considering its relatively small sample (N
235) and require a methodological comment.
The questionnaire we used to measure the occurrence of early traumatic life events explored a variety of adverse experiences other than physical and sexual abuse. There is a large body of evidence in the clinical literature demonstrating that childhood attachment-related trauma 
, such as prolonged separation from parents or chronic conflict within the family (which were the most frequently reported events among the participants of our study), and lack of parental warmth 
can increase the risk for aggressive behavior during adolescence and adulthood. The exclusive or limited focus on physical abuse and maltreatment might in part explain the failure of some previous studies to confirm the role of MAOA genotype in moderating the relationship between early stress and subsequent aggressive behavior 
Another important difference between the present study and previous ones is the measure used to assess the behavioral phenotype. As dependent variable, we used the physical aggression scale of the Aggression Questionnaire 
, a continuous measure that assesses individual propensity toward aggression and that can be administered to individuals in the normative range of aggressive behavior. In contrast, most previous studies have used relatively indirect measures of aggressive behavior, such as incarceration, criminal conviction, or a diagnosis of antisocial behavior or conduct disorder. The problem with these measures is that antisocial behavior or conduct disorder include a number of behaviors other than aggression and that they are dichotomous (presence or absence of the behavioral phenotype), which may lead to a corresponding loss of discriminatory power. Our findings suggest that the use of psychometric tools assessing behavioral aspects of aggression ranging from normative levels to pathological extremes may increase the likelihood of detecting interactions of MAOA genotype with early traumatic events.
This study has several limitations, the first of which is the small sample size. Studies relating genetic polymorphisms to behavioral or self-report assessments typically use much larger samples. Thus, the present results should be interpreted with caution until these findings have been replicated in larger samples. However, the within-study replication in psychiatric patients and healthy volunteers justifies a fairly high level of confidence. Second, we used a retrospective measure to assess the occurrence of traumatic events during childhood. When the type of events assessed is not limited to objective trauma (e.g., death of mother) but also includes perceived situations (e.g., parental marital problems), retrospective data may be subject to faulty recall or systematic distortions, even though the construct validity of our measure of early trauma was supported by its strong association with later-life aggression, in accordance with most other studies related to this topic. Although prospective studies are clearly desirable in delineating the role of early environment in the development of later-life aggressive behavior, such investigations face daunting methodological difficulties. Until such methodological problems can be overcome, reliance will have to be placed on a variety of sources of information, including retrospective data, to study G×E. Third, we used a self-report measure of aggression, and the social desirability bias of some subjects might have affected their self-reporting of aggression. Subjects motivated by need for social approval may not report as much aggression as those to whom social approval is less important. Such a bias, however, probably reduced our ability to detect interaction effects and thus implies that the findings are conservative estimates of G×E. Fourth, we included women in our sample to assess the impact of gender on the MAOA-early trauma interaction. Few studies investigating MAOA-related aggression have included female subjects 
. Inclusion of women in such studies is complicated by the fact that somatic MAOA allele mosaicism, due to X-chromosome inactivation, makes classification of heterozygous females problematic. Previous research has shown that female heterozygotes show patterns of neural activity intermediate between MAOA-L and MAOA-H male hemizygotes and that female homozygotes show patterns of neural activity comparable to male hemizygotes 
. Because, in our sample physical aggression scores were indistinguishable among the three female genotypes, we were not able to draw conclusions about the status of heterozygous female subjects.
In conclusion, despite its limitations, this study supports and extends the findings of previous reports showing that the MAOA polymorphism in combination with early experience modulates individual proclivity to later-life physical aggression. Its major methodological contribution is that the use of continuous self-report measures of aggression ranging from normative levels to pathological extremes and a wider focus in assessing early trauma may increase the likelihood of detecting interactions between the MAOA gene and childhood environment.