Introduction
Antisocial behavior is among the most common reasons for referral to mental health services in adolescence and externalizing disorders often leads to detrimental long-term consequences (Erskine et al.
2016; Hacker et al.
2014). Antisocial behavior is a multidimensional construct that includes a broad range of behaviors, mainly aggression and delinquency (Morizot and Kazemian
2015). In an effort to shed light on the etiology of antisocial behavior, researchers have revealed the role of genetic (explaining 40–60% of the variance) and non-shared environmental factors (explaining 30% of the variance) (Ferguson
2010; Tuvblad et al.
2011; Vitaro et al.
2015). Non-shared environmental factors refer to the environment that is not shared by siblings in a family, such as peer relations, differential parental treatment, accidents, or health issues. Shared and non-shared environmental factors have been thoroughly examined in relation to antisocial behavior and the important role of family and peer relations has been established (Assink et al.
2015). Research has also focused on identifying specific genes that contribute to the development of antisocial behavior, indicating that a region in chromosome 2 (2p12) and variation within AVPR1A might be associated with antisocial behavior (Pappa et al.
2016). There is also growing evidence on the effects of gene-environment interactions between specific genes and environmental factors on antisocial behavior, focusing, among others, on deviant peer affiliation, as it is one of the stronger predictors of adolescent antisocial behavior (Vitaro et al.
2015). However, there is a lack of research on potential gene-environment interaction effects between the oxytocin receptor gene (
OXTR) and deviant peer affiliation in antisocial behavior, despite
OXTR’s association with antisocial behavior as well as social affiliation and bonding.
The
OXTR gene is the encoded receptor for the neuropeptide oxytocin, which is involved in social-affective behaviors, such as prosocial behavior, social affiliation, attachment, and pair bonding (Lee et al.
2009). Experimental studies have indicated that intranasal administration of oxytocin enhances empathy, emotion recognition, trust, and generosity, and reduces stress reactivity (Guastella and MacLeod
2012; Veening and Olivier
2013). Importantly, this effect was more pronounced in individuals with social-affective deficits (Bartz et al.
2011). Abnormal oxytocin levels have also been found in patients with ADHD, conduct disorder, and psychopathy, but the results have been contradictory, demonstrating both higher and lower oxytocin levels in patients compared to controls (see for a review Fragkaki et al.
2017).
Furthermore, the
OXTR gene is expressed in the brain and several other tissues, but its anatomical distribution varies considerably across species and affects the social organization of each species (see for a review Vaidyanathan and Hammock
2016). Developmental experiences and epigenetics can alter
OXTR expression in adulthood leading to impairments in social behavior.
OXTR expression and distribution differ across development and it has been proposed that “
OXTR may be a developmental plasticity gene that serves as a transducer of the social environment to fine-tune the experience-dependent plasticity of the social brain” (Vaidyanathan and Hammock
2016). More specifically, a transient profile of
OXTR mRNA has been observed in the human neocortex and it has been argued that oxytocin plays a crucial role in the processing of socially contingent sensory information in the neocortex (Vaidyanathan and Hammock
2016). Indeed, genetic studies have shown associations between
OXTR and social behavior, pair bonding, social cognition, social interaction, and social support, especially for the single nucleotide polymorphisms (SNPs) rs53576 and rs2254298, although the results were inconsistent (Bakermans-Kranenburg and Van IJzendoorn
2013; Ebstein et al.
2012). Based on these findings and taking into account that individuals with antisocial behavior are characterized by social-affective deficits, research has explored whether antisocial behavior might be related to variations within the
OXTR.
Several studies have addressed this question by examining
OXTR variations in healthy and antisocial individuals. Findings from healthy samples revealed significant effects of
OXTR polymorphisms on antisocial behavior in young males (Hovey et al.
2015; LoParo et al.
2016). Particularly, the C allele of the rs4564970 and the AA genotype of the rs7632287 were related to aggression and rs7632287 AA was associated with delinquency in boys only in a large sample of 2372 individuals and a replication sample of 1232 individuals, including adolescents and young adults (16–20 years) (Hovey et al.
2015). A 6-factor model for
OXTR was also associated with aggression and interacted with alcohol in 235 males aged 18–32 years in response to aggression provocation (LoParo et al.
2016). Another study showed that male carriers of the A allele of rs1042778 had higher right amygdala reactivity in response to angry faces which was related to higher levels of antisocial behavior in a sample of 406 healthy young adults aged 18–22 years (Waller et al.
2016). Overall, the evidence so far suggested an association between genetic variations in
OXTR and antisocial behavior in healthy samples.
Previous studies on clinical samples with antisocial behavior have also yielded significant associations with
OXTR polymorphisms. In specific, the C allele of rs1042778 as well as the haplotypes CG of rs1042778 and rs6770632, and CT of rs1042778 and rs53576 were more prevalent in aggressive boys, whereas the A allele for rs6770632 was more prevalent in aggressive girls in 160 children and adolescents with disruptive disorders compared to 160 healthy adults (Malik et al.
2012). However, the findings did not survive multiple correction testing when compared to 182 healthy children (Malik et al.
2014). A recent study found increased conduct problems at age 15 in rs53576 G carriers in a sample of 404 adolescents with high levels of maternal depression (Smearman et al.
2015). In contrast, another study examined the effects of 10 single nucleotide polymorphisms in 1750 adolescents with substance and behavioral problems and found no significant effects of the 10 single nucleotide polymorphisms in relation to conduct disorder (Sakai et al.
2012). It is noteworthy that the aforementioned studies showed various
OXTR polymorphisms in relation to antisocial behavior, but the results did not consistently support the central role of specific single nucleotide polymorphisms. These mixed findings suggest the contribution of small effects of several single nucleotide polymorphisms rather than the role of one specific single nucleotide polymorphism in antisocial behavior.
Additionally, the complexity of antisocial behavior should be taken into account in the interpretation of the findings. Although aggression and delinquency are central components of antisocial behavior, there are more specific subtypes, such as types of aggression and psychopathic traits. Particularly, two types of aggression are often distinguished, reactive and proactive aggression. Reactive aggression is an impulsive response to threat, provocation, or frustration and it is accompanied with anger, whereas proactive aggression is planned and driven by the achievement of a goal or a reward (Vitaro et al.
2006). These two types of aggression have distinct characteristics and are related to different social, cognitive, emotional, and physiological processes and outcomes (Hubbard et al.
2010).
More specifically, reactive aggression is associated with anger, peer rejection, internalizing problems, paranoid personality traits, bad quality of parent-child relationship, lower number of friends, and higher physiological arousal after provocation (Hubbard et al.
2010). In contrast, proactive aggression is not related to anger, internalizing problems, or bad quality of parent-child relationship but rather the lack of parental monitoring. It is characterized by a lack of physiological arousal in response to provocation (Hubbard et al.
2010) and it is linked to antisocial but not paranoid personality traits (Lobbelstael et al.
2015). In addition, distinct deficiencies in social information processing have been found in reactive and proactive aggression, indicating that reactive aggression is linked to impairments in encoding and interpretation of cues, whereas proactive aggression is linked to impairments in clarification of goals, response access, and response decision (Kempes et al.
2005). Most importantly, although both types are influenced by genetic and environmental factors, the stability of proactive aggression over time is more strongly explained by genetic factors than the stability of reactive aggression (Tuvblad and Baker
2011). In addition, proactive aggression is behaviorally and genetically linked to callous-unemotional traits and psychopathy (Bezdjian et al.
2011; Cima and Raine
2009), which are characterized by shallow emotion, lack of empathy, shame, or guilt and are related to more severe antisocial behavior and stronger biological underpinnings (Frick et al.
2014). Overall, distinct characteristics between reactive and proactive aggression have been revealed, underscoring the different processes associated with each type and suggesting a stronger biological background for proactive aggression compared to a more environmental background for reactive aggression.
Taken together, the findings, although promising, do not provide a clear picture of the genetic contribution of OXTR in antisocial behavior. First, the aforementioned studies showed various risk alleles in different types of antisocial behavior. Second, previous studies did not systematically include several types of antisocial behavior, raising the question of whether OXTR variations are linked to antisocial behavior as a construct or to specific types of antisocial behavior.
In a similar vein, the gene-environment interaction between
OXTR and deviant peer affiliation has not been explored yet. Considering that
OXTR is related to social affiliation and bonding, and that peer affiliation is a fundamental expression of social relationships in adolescence, it is crucial to explore whether
OXTR interacts with deviant peer affiliation in the development of antisocial behavior. Deviant peer affiliation has been widely established as one of the strongest non-shared environmental predictors of antisocial behavior in adolescence (Dishion et al.
1995; Vitaro et al.
2015). However, it is also influenced by genetic factors, especially in adolescence (Connolly et al.
2015; Vitaro et al.
2015). In addition, there is increased support for gene-environment interactions in antisocial behavior. Gene-environment interaction studies explain their findings in terms of the diathesis stress model (Zuckerman
1999) or the differential susceptibility model (Belsky and Pluess
2009). According to the diathesis-stress model, adolescents with a genetic predisposition toward antisocial behavior are more likely to develop such a behavior when they affiliate with deviant peers (Zuckerman
1999). According to the differential susceptibility model, adolescents with a genetic vulnerability might exhibit more positive behaviors when interacting with a positive environment but more negative behaviors when interacting with a negative environment (Belsky and Pluess
2009). Several previous studies revealed gene-environment interactions in antisocial behavior for several genes, but the results were inconsistent (Vitaro et al.
2015).
It is argued that the investigation of a gene-environment interaction between
OXTR and deviant peer affiliation is crucial due to
OXTR’s involvement not only in antisocial behavior but also in social affiliation, which is under ongoing development during adolescence in form of peer relationships. In an effort to understand the role of oxytocin in social behavior, it has been suggested that oxytocin might modulate the salience of social stimuli in the environment and direct our attention toward them, leading to a better understanding of social cues and thus a more successful formation of social relations (Shamay-Tsoory and Abu-Akel
2016). Another approach posits that oxytocin might be related to self-referential processing and interoception that may contribute to the development of empathy and promote in-group survival (Hurlemann and Scheele
2016). Additionally, as mentioned above, oxytocin is involved in the development of the social brain (Vaidyanathan and Hammock
2016). Recent animal studies showed that oxytocin release is increased in the ventral tegmental area during social interactions, which in turn increases the activity of dopamine neurons that are involved in social reward, emphasizing the role of oxytocin in social behaviors (Hung et al.
2017). Therefore, oxytocin seems to have a contributing part in the development of social-affective behaviors and especially social relationships.
It is widely known that during adolescence peers exert a great influence on each other and adolescents tend to create in-groups with close friends and conform to the behavioral norms of the group (Steinberg and Morris
2001). Consequently, adolescents who affiliate with deviant peers tend to exhibit also deviant behaviors in order to conform to their friends’ behavior and maintain their peer group. Speculatively, a potential gene-environment interaction of
OXTR and deviant peer affiliation might be driven by
OXTR’s role in the development of the social brain, prosocial behavior, and social affiliation that can interact with the social bonds with peers leading to distinct patterns in antisocial behavior.
Discussion
Gene-environment interactions in antisocial behavior have gained interest and revealed that several genes interact with environmental factors, such as perceived deviant peer affiliation, in the development of antisocial behavior. However, there is one gene that although it has been associated with both prosocial and antisocial behaviors (Bakermans-Kranenburg and Van IJzendoorn
2013; Ebstein et al.
2012; Lee et al.
2009), it has not been investigated in gene-environment interaction studies yet; the
OXTR gene.
OXTR is involved in the development of the social brain (Vaidyanathan and Hammock
2016) and it might affect the formation of social relationships in adolescence, especially peer relations. Given its complex involvement not only in prosocial and antisocial behavior, but also in social affiliation, it seems essential to investigate its interaction with deviant peer affiliation and not only its direct effect on antisocial behavior. The present study aimed to examine whether
OXTR interacts with perceived deviant peer affiliation in antisocial behavior in adolescents aged from 13 to 18, using a longitudinal design and gene-based testing. Importantly, three components of antisocial behavior were examined, reactive aggression, proactive aggression, and delinquency to capture the complexity of antisocial behavior. The findings revealed no main direct effect of
OXTR in antisocial behavior, but a significant gene-environment interaction between
OXTR polymorphisms and perceived deviant peer affiliation in proactive aggression and delinquency.
More specifically, there was no main genetic effect of
OXTR polymorphisms on antisocial behavior, but there was a main effect of perceived deviant peer affiliation on all dependent variables. The role of perceived deviant peer affiliation in antisocial behavior has been well established in previous research (Dishion et al.
1995; Vitaro et al.
2015), but the findings on main effects of
OXTR are inconsistent. Previous research examined various single nucleotide polymorphisms of the
OXTR in relation to antisocial behavior using SNP-based tests and although some studies found significant effects of a limited number of single nucleotide polymorphisms (Hovey et al.
2015; LoParo et al.
2016; Malik et al.
2012; Smearman et al.
2015), others did not find effects that survived correction for multiple testing (Malik et al.
2014; Sakai et al.
2012). In this study, gene-based tests were used to overcome the limitations of SNP-based tests, as they include a number of single nucleotide polymorphisms in one test, increasing the detectability of associations by aggregating small effects and reducing the number of tests (Tzeng et al.
2011). The findings suggest that
OXTR does not have a direct effect on any aspect of antisocial behavior but it rather interacts with perceived deviant peer affiliation. However, it is important to highlight that only five single nucleotide polymorphisms were included that did not provide coverage of the entire
OXTR gene. Speculatively, the addition of more single nucleotide polymorphisms in future gene-based tests might reveal a potential small direct effect of
OXTR. In addition, the sample size was small and did not have the power to detect small direct effects. Considering the role of
OXTR in social behavior and affiliation, the gene-environment interaction of
OXTR with perceived deviant peer affiliation can provide more useful information on how the undeniable role of peers in adolescent antisocial behavior might also be related to the genetic makeup.
This interaction suggests that the effect of perceived deviant peer affiliation on antisocial behavior might be influenced by
OXTR variations. Given that gene-based tests are not direction tests, it is not possible to reveal specific risk alleles, as each single nucleotide polymorphism has its own positive or negative loading (see also LoParo et al.
2016 for a similar methodology). Considering the role of oxytocin in a broad spectrum of social behaviors, such as social affiliation, pair bonding, and trust (MacDonald and MacDonald
2010) as well as
OXTR’s role in the development of the social brain (Vaidyanathan and Hammock
2016), it is possible that variations in
OXTR have a differential effect on the regulation of oxytocin that consequently leads to different interaction effects with peers.
For instance, adolescents with specific
OXTR variations might be more prone to behave similarly to their peers in an effort to seek acceptance and bonding and thus exhibit the same behavior as their peers (positive or negative), supporting the differential susceptibility model. There is evidence indicating that oxytocin administration can enhance trust toward individuals who are seen as trustworthy or belong to the “in-group”, but can have the opposite effect for the “out-group” or toward individuals who are seen as untrustworthy (Bartz et al.
2010,
2011; Van IJzendoorn and Bakermans-Kranenburg
2012). In addition, it has been suggested that oxytocin might be related to self-referential processing and interoception that may promote in-group survival (Hurlemann and Scheele
2016). This raises the question whether
OXTR function might play a role in how adolescents perceive and affiliate with their peers compared to the “rest of the world”. They might trust their in-group of peers and exhibit matching behaviors. They potentially perceive as untrustworthy those who are considered to be outside of their in-group circle and simultaneously exhibit aggressive behavior toward them. This potential explanation, however, is based on previous studies on oxytocin administration and not on genetic variations of
OXTR. A further and closer investigation of this gene-environment interaction could shed additional light on how
OXTR affects the formation of peer relationships, in-group and out-group trust, as well as the paths toward antisocial behavior.
In addition, this gene-environment interaction might be driven by the link between oxytocin and prosocial behavior. Transient
OXTR expression during neocortical development might increase neural activity in response to multisensory inputs and shape the processing of social inputs (Vaidyanathan and Hammock
2016). A specific brain activation network has been identified in empathy, consisting of the anterior midcingulate cortex (aMCC), the dorsal anterior cingulate cortex (dACC), the dorsal-caudal edge extending to supplementary motor area (SMA), and bilateral anterior insula (Fan et al.
2011). Moreover, it has been suggested that the development of empathy emerges very early in life and can be detected in neurophysiological patterns in infancy (Tousignant et al.
2017), a period with increased
OXTR expression in the neocortex. Previous genetic studies have also shown that
OXTR variations are associated with empathy (Rodrigues et al.
2009; Uzefovsky et al.
2015) and oxytocin administration enhances empathy and emotion recognition especially in individuals with social-affective deficits (Bartz et al.
2011).
It is hence possible that OXTR variations might be related to impairments in empathy and prosocial behavior that could relate to the development of antisocial behavior. Speculatively, this effect might interact with the social environment and lead to the development of antisocial behavior only when adolescents affiliate with deviant peers, supporting the diathesis-stress model. Alternatively, the differential susceptibility model might also be in place. Positive peer affiliation might be beneficial for the development of empathy and prosocial behavior, especially in youth with social deficits, whereas deviant peer affiliation might reinforce these deficits and lead to antisocial behavior. Overall, there are several interesting approaches to interpret this gene-environment interaction, but they merit further exploration to draw solid conclusions. It would be especially beneficial to examine this gene-environment interaction not only in relation to perceived deviant peer affiliation but also in relation to positive and supportive peer groups to decipher whether this interaction supports the diathesis-stress model or the differential susceptibility model.
It is important to mention that the results remained significant for proactive aggression but not for reactive aggression after correction for multiple testing. These two types of aggression have distinct characteristics and are related to different processes and outcomes (Hubbard et al.
2010). A recent study found a gene-environment interaction between Monoamine Oxidase A (
MAOA) and Catechol-O-Methyltransferase (
COMT) genes and parenting on reactive aggression but not on proactive aggression, highlighting the differential genetic contribution of these two types of aggression (Zhang et al.
2016). In the present study,
OXTR interacted with deviant peers on proactive aggression but not on reactive aggression, suggesting that this interaction might be specific to proactive aggression. However, the corrected alpha level was .06 for reactive aggression, which advise us to interpret this finding with caution. It is possible that this result would remain significant in a larger study and hence it seems imperative to replicate it in larger studies before drawing solid conclusions.
Moreover, the gene-environment interaction did not predict how antisocial behavior changed over time. Previous research yielded different trajectories of antisocial behavior over the course of adolescence that usually included multiple classes (Reef et al.
2011; Van Lier et al.
2007). The present sample size was not large enough for a latent class analysis and it is possible that the gene-environment interaction might be significant for specific classes but not for the total sample. Using the overall change over time, it is not possible to detect a specific effect of the interaction in a particular class. Larger studies are highly needed to unravel whether this gene-environment interaction affects a specific class of antisocial behavior. Importantly, the gene-environment interaction on the intercept indicates that
OXTR variations interact with perceived deviant peer affiliation in early adolescence (age 13). It has been posited that childhood-onset antisocial behavior is more severe, has more adverse outcomes, and is more biologically driven compared to adolescent-onset antisocial behavior (Moffitt et al.
1996). In line with this theory, it is possible that genetic contributions and interactions with perceived deviant peer affiliation are more relevant in antisocial behavior at an early age and might be indicative of more severe antisocial behavior.
In addition, a study suggested that the effect of deviant peer affiliation, although substantial, it might have been overestimated in previous studies and the effects of social control processes might have been underestimated (Haynie and Osgood
2005). The authors found that the effects of peer delinquency and unstructured socializing on delinquency were comparable. Taking into account the development of self-regulation and inhibitory control from childhood to adolescence (Steinberg
2008), the role of psychosocial immaturity in persistent antisocial behavior (Monahan et al.
2013) as well as the genetic contribution to inhibitory control (Weafer et al.
2017), it is reasonable to assume that younger adolescents might be more prone to gene-environment interactions with peers compared to older adolescents especially in unstructured settings. It would be interesting for future research to explore this gene-environment interaction in younger children and also incorporate other social control contexts to better understand the developmental process of this interaction.
Finally, the developmental trajectories of antisocial behavior showed that reactive aggression decreased over time, whereas proactive aggression and delinquency remained stable. Previous research has identified multiple classes in aggression and delinquency, suggesting the presence of stable low or moderate levels, increasing levels, or stable high levels of antisocial behavior in adolescence (Landsheer and van Dijkum
2005; Reef et al.
2011). Specifically, for reactive and proactive aggression, a study found that in proactive aggression, the majority of adolescents exhibited a low stable trajectory, followed by adolescents with moderate stable and high peaking proactive aggression (Barker et al.
2010). In reactive aggression, the majority of adolescents exhibited a moderate desisting pattern, followed by low stable and high peaking patterns. In addition, proactive aggression is related to and predictive of delinquency in adolescence and they seem to follow similar trajectories (Hubbard et al.
2010).
It has been suggested that reactive aggression, but not proactive aggression is highly associated with peer rejection and victimization (Hubbard et al.
2010). As adolescents grow older, they develop more efficient coping strategies and peer victimization and physical fighting decrease as they learn to use these coping strategies in conflict resolution (Compas et al.
2017; Rudatsikira et al.
2008; Zimmer-Gembeck and Skinner
2016). It is thus possible that the decrease of reactive aggression might be explained by the development of coping strategies in late adolescence that have been related to lower levels of psychopathology (Compas et al.
2017). In contrast, proactive aggression, especially at a young age, is related to callous-unemotional traits and psychopathy in adulthood, more adverse outcomes in the long run, and higher levels of antisocial behavior and delinquency (Frick et al.
2014). Importantly, the stability of proactive aggression over time is more strongly explained by genetic factors than the stability of reactive aggression (Tuvblad and Baker
2011). Overall, the findings are in line with previous studies on developmental trajectories of antisocial behavior, although specific classes were not examined as they were out of the scope of this study.
Several limitations of this study should also be mentioned to better understand the generalizability of the findings and suggest useful directions for future research. First, a community sample of adolescents who were at risk of externalizing problems were recruited but they were not clinical patients and the sample size was small. Genetic studies using larger samples and clinical populations are necessary to confirm the present findings and examine whether this interaction is different in clinical populations. Second, this study did not have the power to examine gender differences that have been found in previous research with SNP-based tests. Speculatively, this gene-environment interaction may be more pronounced in males given the stronger evidence of a direct effect of
OXTR in antisocial behavior as well as the higher rates of antisocial behavior and deviant peer affiliation in boys and male adults. Relatedly, the sample lacked the power to examine classes of trajectories that might be specifically related to the gene-environment interaction under investigation. Third, although gene-based tests that are advantageous compared to SNP-based tests were used, a small number of single nucleotide polymorphisms was included in this study. The inclusion of five single nucleotide polymorphisms was based on their associations with social and antisocial behavior in previous research as well as their role in the expression of the gene as a meaningful and economical first step toward exploring this gene-environment interaction. The inclusion of a large number of single nucleotide polymorphisms in future gene-based tests is highly recommended, as it would provide a more robust measurement of the
OXTR gene. Fourth, this study recruited a sample of adolescents aged 13 to 18, but it would be very elucidating for future studies to explore different developmental trajectories from an earlier age. Fifth, an indirect measurement of deviant peer affiliation was used in this study, which is not the optimal methodology. It has been proposed that indirect measurements of peer delinquency suffer from several shortcomings (Young et al.
2015), which should be taken into account when interpreting the findings of this study. The measurement used in this study has been examined in comparison to direct measures of peer delinquency and the authors concluded that indirect measures were reliable but might underreport peer delinquency, potentially because responders might not be aware of all the delinquent acts committed by their friends (Weerman and Smeenk
2005). Sixth, this study was focused on perceived deviant peer affiliation, but this is only one aspect of peer affiliation. Future studies should also investigate potential gene-environment interactions with perceived peer support and more positive peer groups. Last but not least, given the role of
OXTR in social and prosocial behavior, it is essential for future research to examine more potential gene-environment interactions of
OXTR with other socially relevant environmental factors that could be involved in antisocial behavior, such as family relations or parental style.