4.3. Externalizing behaviors

As mentioned previously in the ADHD section, ADHD is often accompanied by ODD starting in early childhood, and by CD diagnosed in late childhood – adolescence or by APD diagnosed after age 18 (Biederman, 2005). According to DSM-IV (American Psychiatric Association, 1994), ODD is characterized by negativistic, hostile, and defiant behaviors (e.g., actively defying or refusing to comply with adults requests or rules, deliberately annoying people, blaming others for his or her mistakes or misbehavior). Whereas CD symptoms include aggressive and destructive behaviors (e.g., cruel behavior toward people or animals, destruction of property, stealing), and violations of rules. After the age of 18, CD may develop into APD, which is characterized by the above mentioned aggressive and destructive behaviors with an apparent lack of remorse. APD symptoms can also include recurring difficulties with the law, irresponsible work behavior, and abusive relationships. It has been shown that childhood ADHD predicts adult substance abuse, but it has also been demonstrated that early intervention and treatment in ADHD can prevent later illicit substance abuse during adolescence (Faraone and Wilens, 2003). Externalizing disorders, such as CD, APD, and substance abuse showed 80% heritability in a large-scale twin study conducted among 542 families (the Minnesota Twin Family Study, Hicks et al., 2004). Using a quantitative genetic model, the same workgroup could detect a gene × environment interaction in the development of externalizing disorders showing that genetic factors exhibited a greater effect under environmental adversity (Hicks et al., 2009). Using candidate gene analyses, a reproducible gene × environment interaction involving the MAOA uVNTR and childhood adversities has been shown for antisocial behaviors in independent association studies (reviewed by Thapar et al., 2007).

In a large Dutch family study a rare mutation in the X chromosome indicated that MAOA is involved in aggressive behavior, because aggressive and violent behavior was observed in MAOA deficient men (Brunner et al., 1993). Later, an animal study supported this observation as mice lacking the MAOA enzyme also exhibited enhanced aggression during adulthood (Cases et al., 1995). Since the gene encoding MAOA is localized on the X chromosome, robust effects are usually observed in males. In addition, it is not recommended to include heterozygote females in the analyses because of the potential inactivation of one of the X chromosomes; therefore, most association studies included only male subjects. The first study reporting gene × environment interaction regarding the MAOA uVNTR and childhood maltreatment showed that males with the low-activity MAOA genotype in the severe maltreatment group were more likely to develop CD in adolescence, had more APD symptoms at age 26, and were convicted for violent offence more frequently compared to those maltreated subjects with the high-activity MAOA genotype (Caspi et al., 2002). Although some subsequent studies reported negative findings concerning the interaction between the MAOA genotype and childhood maltreatment, the results of a meta-analysis supported the original finding (Taylor and Kim-Cohen, 2007). A recent study suggested that this interactive effect of MAOA and childhood maltreatment can be observed only at moderate levels of trauma exposure, because extreme levels of trauma appear to overshadow the effects of MAOA genotype (Weder et al., 2009). The underlying neural mechanisms responsible for the MAOA findings have been localized in the limbic system, as low-activity MAOA genotype men had a reduced limbic volume and a higher amygdala responsiveness during emotional arousal (Meyer-Lindenberg et al., 2006).

MAOA metabolizes serotonin and norepinephrine in addition to dopamine, thus the MAOA genetic findings could be attributed to other monoamine theories. For purely dopaminergic genes, the picture is less clear: three longitudinal, general population-based studies and three clinical sample-based studies investigating adolescents with ADHD or CD resulted in contradictory findings for the DAT1 3′ UTR VNTR. The 9-repeat allele or the 9/10 genotype (vs. 10/10) was associated with higher levels of externalizing symptoms (Young et al., 2002, Barkley et al., 2006), but this finding was not supported by later studies using either community-based samples (Jorm et al., 2001; Caspi et al., 2008) or clinical samples (Caspi et al., 2008; Schulz-Heik et al., 2008). One possible explanation for these contradictory findings may be the distinct underlying factors for violent, physically aggressive behaviors, and for non-aggressive, rule-breaking antisocial behaviors. This explanation was presented by Burt and Mikolajewski (2008), who reported that more rule-breaking behavior was observed in male undergraduates with the DAT1 10/10 genotype than those without this genotype. At the dopamine receptor genes, a gene × gene interaction was described in connection to adolescent CD problems and adult antisocial behaviors in a large, population-based study: males with the DRD2 A1-allele and DRD4 7-repeat allele showed more CD symptoms (Beaver et al., 2007).

In terms of the COMT Val158Met polymorphism, CD and APD were studied in the general population (birth cohorts) and among subjects diagnosed with ADHD. The Val/Val genotype was repeatedly associated with more CD and aggressive symptoms among children with ADHD (Caspi et al., 2008; Monuteaux et al., 2009; DeYoung et al., 2010) but not among children without ADHD (Caspi et al., 2008). In addition to the association of CD symptoms and the COMT Val/Val genotype in ADHD children, there was a gene × environment interaction described: children with the Val/Val genotype were more susceptible to the adverse effects of prenatal risk as indexed by lower birth weight (Thapar et al., 2007). Other gene × environment interaction findings in connection to antisocial behavior among ADHD children were also reported in the Cardiff ADHD genetic study, for example between DAT1 and DRD5 polymorphisms and maternal smoking during pregnancy (Thapar et al., 2007). Future analyses from independent studies are needed to support these findings.