The results of the current study showed that, in a sample of students enrolled in a large Midwestern university, PSU was predicted by the interaction of MAOA uVNTR allelic variants, sex, and specific child maltreatment types. The highest number of substances used was found in MAOA-L male and MAOA-HH female carriers with a history of emotional abuse (as well as physical abuse in women). To our knowledge, this is the first report documenting a key role of MAOA as a mediator of child maltreatment with respect to PSU. While previous studies have shown the importance of G×E interactions in PSU (Vaughn et al., 2009; Rende, 2011), the specific genetic factors implicated in such biosocial interplays remain mostly elusive; if confirmed by future studies, our results may point to MAOA as a key molecular basis for PSU.

The present findings extend our previous report of sex-dimorphic influences of G×E interactions in the lifetime use of tobacco (Fite et al., 2018) among college students. Furthermore, these results are consistent with previous evidence indicating sex differences in the interactive influence of these G×E interactions with respect to antisocial conduct (Nikulina et al., 2012; Stogner and Gibson, 2013; Byrd and Manuck, 2014; Harro and Oreland, 2016) and alcohol use (Nilsson et al., 2011). The interaction of MAOA alleles and child maltreatment can be interpreted from the perspective of the diathesis-stress model, which postulates that the predisposition to specific neurobehavioral deficits is the result of a synergistic combination of genetic and environmental untoward factors (Zuckerman, 1999). Another alternative interpretation follows the differential susceptibility hypothesis, which posits that specific genetic variables may sensitize to both the positive and the negative influence of early experiences (Ellis et al., 2011). This possibility is partially supported by Belsky and colleagues (Belsky et al., 2009; Belsky and Beaver, 2011), who have conceptualized that MAOA variants may act as plasticity factors in the predisposition to substance use and other psychopathological conditions.

In line with previous data (Armour et al., 2014), the current results highlight the importance of examining specific maltreatment types in relation to PSU. Our findings suggest that, although physical abuse and emotional abuse interact with MAOA variants to predict PSU even when statistically controlling for the other maltreatment types, no interaction effects were found for sexual abuse, physical neglect, or emotional neglect. This evidence is partially consistent with a previous study by Nikulina and colleagues (2012) suggesting that MAOA does not serve as a protective or risk factor for substance use outcomes among individuals who have experienced childhood sexual abuse. However, in contrast with our results, the results of that investigation showed that alcohol use was not predicted by the interaction of MAOA with either physical abuse or neglect. Given that the participants of that study ranged between 31 and 51 years of age, it is possible that the discrepancy with those results may reflect age differences; accordingly, the moderating effect of MAOA on child maltreatment and negative outcomes has been hypothesized to be age-dependent (Huizinga et al., 2006). Alternatively, these divergent findings may result from other differences between our studies, including the substance use outcomes (i.e., PSU vs alcohol abuse) and measurement of child maltreatment (i.e., self-report vs official records). Nevertheless, research shows that experiences of child maltreatment are associated with decreased propensity for reward selection, which could be due to lower reward sensitivity (Guyer et al., 2006). In turn, this dual risk might increase the risk of PSU. Thus, child maltreatment types, physical abuse and emotional abuse may be more saliently associated with blunted reward sensitivity.

The existence of sex-dimorphic G×E interactions involving MAOA uVNTR alleles has been attested in other psychopathological states. For example, male carriers of MAOA-L alleles with a history of child maltreatment have a significantly higher risk of antisocial, aggressive, and violent behavior (Caspi et al., 2002; Kim-Cohen et al., 2006; Beaver et al., 2010; Aslund et al., 2011; Fergusson et al., 2011; Fergusson et al., 2012; Byrd and Manuck, 2014; Godar et al., 2016). Notably, the same G×E interaction has been reproduced in mouse models, further supporting the biological nature of this biosocial interplay (Godar et al., 2019). Conversely, female carriers of MAOA-H alleles with a positive history for early-life adversity display a higher proclivity for antisocial and violent responses (Sjöberg et al., 2007; McGrath et al., 2012; Verhoeven et al., 2012). It has been hypothesized that this effect may reflect the enhancement of emotional reactivity during adolescence (Byrd et al., 2018). Furthermore, these effects may reflect sex- and genotype-specific differences in the effects of MAOA on monoamine metabolism (Jönsson et al., 2000; Aklillu et al., 2009). Notably, aggression and delinquency have been extensively linked to PSU, particularly in boys (McCormick and Smith, 1995; Mason and Windle, 2002; Martinotti et al., 2009). This concurrence strongly suggests that the G×E interaction of MAOA genotype and child maltreatment may predispose to a broad set of externalizing responses, ranging from antisocial personality to PSU propensity. In line with this interpretation, neuroimaging studies have pointed to MAOA as a key molecule to influence the function of the anterior cingulate cortex (ACC) (Passamonti et al., 2008). This region plays a major role in the regulation of self-regulation (Posner et al., 2007), the key domain implicated in the ontogeny of antisocial behavior (Gardner et al., 2008; Trentacosta and Shaw, 2009; Gillespie et al., 2018), as well as in the role of G×E interactions in PSU (Vaughn et al., 2009). The effects of MAOA on ACC activation patterns are sex-dimorphic; specifically, MAOA-L male and MAOA-H female carriers with a history of early stress display impairments in the activation of the ACC in response inhibition (Holz et al., 2016), a process directly related to self-regulation (Posner and Rothbart, 1998; Blair and Ursache, 2011; Hofmann et al., 2012). It should be noted that functional deficits of the ACC are associated with a reduction in inhibitory control (Bush et al., 2000; Chan et al., 2011), as well as a facilitation of ventral striatal responses to incentive stimuli, which in turn increases drug use propensity (Holmes et al., 2016; Koyama et al., 2017). Notably, these deficits may be particularly overt in young individuals (and therefore highly relevant in the age range of college students), due to their incomplete myelination of the ACC as well as the development of the dopaminergic system, which further exacerbates their proclivity to engage in impulsive and risky actions and heightens their reward sensitivity (Casey et al., 2008; Steinberg, 2008). At least in females, the presence of MAOA-H alleles may further reduce dopamine levels, ultimately promoting the ontogeny of reward deficiency syndrome (Blum, 2017; Blum et al., 2018). From this perspective, these results suggest that the interaction of MAOA-L alleles in males and MAOA-H in females and early-life maltreatment may interfere with the development of inhibitory control in emerging adulthood, ultimately increasing PSU risk.

Several limitations of this study should be acknowledged. First, our analyses focused exclusively on MAOA polymorphisms, yet several studies point to the importance of many other genes in the vulnerability to PSU, such as those encoding for dopamine receptor 2 and 4 as well as dopamine and serotonin transporters (Blum et al., 2010); further studies are needed to evaluate the potential interaction of child maltreatment with these vulnerability factors. Second, although rich literature has documented that MAOA variants interact with childhood maltreatment to increase the propensity for externalizing behaviors, our findings need to be replicated in larger samples from multiple colleges and with less skewed ethnic distribution. Indeed, our sample comprised of predominantly Caucasian youth, which may limit the generalizability of current results. Second, this study relied solely on self-reports of constructs, with a low internal consistency associated with our measure of physical neglect. Future research examining associations in other samples (e.g., clinical and criminal) using multiple, psychometrically sound assessments of constructs would be useful for establishing generalizability of findings. Finally, our research combined two- and three-repeat variant carriers in the MAOA-L group; however, previous studies, however, have shown that, in males, two-repeat alleles resulted in much lower levels of promoter activity as well as stronger phenotypic effects than the three-repeat genotype (Sabol et al., 1998; Guo et al., 2008). Notably, two-repeat variants have shown to increase antisocial phenotypes, including the propensity to engage in particularly violent conduct (such as shooting and stabbing), in African-American males (Beaver et al., 2013; Beaver et al., 2014). Unfortunately, given that only one male participant was found to carry the two-repeat alleles, our analyses were not sufficiently powered to differentiate across specific genotypes; however, future studies will be needed to verify whether specific differences may be identified with respect to the interaction of specific variants with early maltreatment.

Despite these limitations, the current study contributes to the growing literature indicating sex differences in genetic risk of MAOA in addition to the importance of the interactive influences of genetic and environmental risk for PSU. Further, findings indicate the importance of evaluating specific maltreatment types to better understand MAOA and maltreatment interactive risks for substance use.