The Monoamine Oxidase A Gene and Antisocial Outcomes : An Examination of Genetic, Epigenetic, and Environmental Factors

Abstract: Background. Antisocial behaviour involves violation of the basic rights of others or social norms or rules. Such behaviours are indexed in diagnoses such as conduct disorder (CD) in adolescence and antisocial personality disorder (ASPD) in adulthood, which are typified by comorbidity with mood, anxiety, and substance misuse disorders. Alcohol misuse is strongly associated with antisocial behaviour and persistent aggressive behaviours. How environmental and biological factors interface to modulate risk for these outcomes is not yet understood, however, the interaction of adversity with a variable number tandem repeat (uVNTR) polymorphism of the monoamine oxidase gene A (MAOA) gene associates with antisocial behaviour and mental disorders. Further, DNA methylation in a region of interest (ROI) spanning MAOA’s first exonic/intronic junction associates with ASPD in men as well as other mood, anxiety, and substance misuse disorders. Aim and Methods. We characterized methylation of the MAOA ROI by sex and age and examined how negative and positive environmental factors interact with MAOA genotype and methylation on antisocial phenotypes and mental disorders. Participants included men and women from a clinical population of young adults recruited in adolescence at a substance misuse clinic and a community sample of adolescents. Findings. (1) Sex but not age was associated with methylation levels such that high methylation levels among women likely represent X-chromosome inactivation, and sexual abuse was associated with hypermethylation of the MAOA first exon, (2) high methylation levels mediated associations between sexual abuse and current depression diagnosis in women, (3) the highest levels of aggressive behaviour were found among maltreat male carriers of the low-expressing MAOA-uVNTR allele and displayed high levels of exonic methylation, while no interactions were shown in women, and (4) among adolescent girls, but not boys, positive parent-child relationship attenuated the interaction of maltreatment and the high-expressing MAOA-uVNTR allele on alcohol consumption, though the interactions were not robust to adjustments for tobacco use, substance misuse, and delinquent behaviours.Conclusion. The findings presented here advance our understanding of how maltreatment interfaces with genotypic and epigenetic factors, in a sex-dependent manner, to promote aggressive behaviour and mental disorders among susceptible individuals.