Adolescent conduct disorder (CD) and adult antisocial behavior are highly heritable phenotypes. Studies using twin designs and model-fitting techniques indicate that up to 85 percent of the variance in these disorders may be attributable to genetic influences[1
]. However, the precise genetic polymorphisms implicated in the etiology of antisocial behaviors remain elusive. The most consistent findings suggest that genes related to the modulation of neurotransmitters may be associated with the development of maladaptive behaviors. For example, in a multivariate analysis of associations, Comings and his coauthors[3
] examined 42 dopamine, serotonin, and norepinephrine genes on attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and CD phenotypes. Their analyses revealed that CD was associated with multiple hormone and neuropeptide genes (CCK, CYP19, ESR1, and INS). In a similar vein, Caspi et al[4
] examined whether the monoamine oxidase A (MAOA) polymorphism was associated with different types of antisocial conduct. Their analysis of 442 Caucasian males from the Dunedin Longitudinal Study revealed that MAOA did not have a significant direct effect on criminal or violent behaviors. However, MAOA interacted with childhood maltreatment to predict variation in criminal behavior. Other studies on MAOA have produced mixed results [5
Taken together, empirical evidence suggests that antisocial conduct constitutes a polygenic phenotype, with the effects of some polymorphisms conditioned by the possession of other polymorphisms – that is, a gene × gene interaction[3
]. However, we know of no research that has reported a gene × gene interaction on a CD behavioral phenotype. Limited evidence suggests that some genes and some proteins may act synergistically to create certain diseases and disorders[8
]. MnSOD and GPX-1, for example, have been found to interact to increase the risk of developing breast cancer[9
The most compelling evidence to suggest that gene × gene interactions may be implicated in the development of certain phenotypes comes from three studies. The first study, conducted by Noble and colleagues[10
], examined the effect that two dopamine receptor genes (DRD2 and DRD4) had on personality traits. The results of their analysis revealed a significant interaction between minor variants of the DRD2 gene and the 7-repeat allele of DRD4 in the creation of novelty seeking. Another set of researchers attempting to replicate this finding failed to detect a significant gene × gene interaction[11
The second study, carried out by Carrasco et al[12
] examined the independent and interactive effects of DRD4 and DAT1 on ADHD in a sample of Chilean families. They employed a family-based discordant sib-pair analysis, which indicated that DRD4 and DAT1 failed to have significant and independent effects on ADHD. However, individuals who possessed both the 7-repeat allele of the DRD4 gene and the 10-repeat allele of the DAT1 gene were significantly more likely to be diagnosed with ADHD (odds-ratio = 12.71) when compared to those subjects with none or just one of these risk alleles.
In the third study, Eisenberg and his colleagues[13
] analyzed data drawn from a sample of college students to estimate the effects of DRD2 and DRD4 on a behavioral measure of impulsivity. The results of their study revealed that DRD2 had a statistically significant main effect on impulsivity, but DRD4 did not. Additional analyses indicated that DRD2 and DRD4 interacted to predict variation in the measure of impulsivity.
Together these three studies provide some empirical evidence indicating that dopaminergic genes may interact to produce novelty-seeking, ADHD, and impulsivity. These findings are particularly important in selecting genetic polymorphisms that may also be implicated in the development of antisocial phenotypes because ADHD and impulsivity are highly comorbid with aggression and violence[14
]. Moreover, several recent studies have revealed that the covariation among ADHD, impulsivity, conduct disorder, and oppositional defiant disorder is due, in large part, to shared genetic effects[15
]. Thus genes that are associated with ADHD may also be the same genes that are associated with antisocial behavioral phenotypes.
Even though significant gene × gene interactions have not been extended to an antisocial behavioral phenotype, a number of lines of research converge to show that dopaminergic polymorphisms have independent effects on a wide array of maladaptive and antisocial phenotypes, such as compulsive gambling, alcohol consumption, and antisocial personality traits[3
]. These studies suggest that dopaminergic genes may be etiologically related to conduct disorder and to antisocial behavior. From this research, two genetic polymorphisms have been identified as potentially important contributors to antisocial phenotypes: the dopamine D2 receptor gene (DRD2) and the dopamine D4 receptor gene (DRD4). DRD2 is a member of the D2 receptor family and has been mapped to chromosome 11 at location 11q23[20
]. DRD2 codes for the D2 receptor and is found throughout the body, but especially in the striatum, the pituitary gland, the amygdala, the caudatus, the putamen, and other regions of the brain[22
The A-1 allele of the DRD2 gene is considered the risk allele for antisocial phenotypes. Research investigating the functional role of the A-1 allele has found that carriers of this allele, in contrast to carriers of the A-2 allele, have fewer brain D2 dopamine receptors[23
], have diminished glucose metabolism in the brain[25
], are more attuned and responsive to stress[26
], and exhibit reduced dopaminergic activity in the central nervous system[23
]. As a result of the findings from these studies, the A-1 allele of DRD2 has been tagged as a contributor to the "reward deficiency syndrome" of the human body[27
DRD4 has been mapped to chromosome 11 at location 11p15.5[29
]. Similar to DRD2, DRD4 also belongs to the D2 dopamine family but manufactures the D4 dopamine receptor protein instead of the D2 dopamine receptor protein. The D4 dopamine receptor protein is found in areas of the brain that are responsible for the expression of emotions and for the stimulation of cognitive faculties[30
]. Like other genes in the dopaminergic system, the DRD4 gene regulates attention processes, is partially responsible for motivation, and has been linked to exploratory behaviors[30
]. The 7-repeat allele has been shown to mediate a blunted intracellular response to dopamine and may also encode a postsynaptic receptor that is subsensitive to dopamine[31
]. The DRD4 polymorphism is one of the most promising candidate genes to many behavioral, psychiatric, and neuropsychological disorders[32
In this study, we test whether DRD2 and DRD4 are associated with multiple measures of conduct disorder and with a measure of antisocial behavior. A considerable amount of research reveals, however, that complex phenotypes, such as antisocial behavior, are probably due to multiple genes acting not only independently, but also interactively. As a result, we also examine the possibility that DRD2 and DRD4 interact to increase the likelihood of evincing signs of antisocial behavior.