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.
Novelty seeking
One possible dimensional approach to impulsive traits and substance use disorders is the assessment of risk-taking behaviors (defined as high levels of risk-taking, exploration, and novelty or sensation seeking). These behaviors are especially characteristic of adolescence (Romer, 2010), and it would be useful to conduct a longitudinal study related to genetic vulnerability; however, most of the genetic association studies are carried out in young adult (student) populations. Several studies have shown that individuals exhibiting high novelty or sensation seeking personality traits are at an increased risk for using drugs of abuse (Bardo et al., 1996; Zuckerman and Kuhlman, 2000). Studies have consistently shown that polysubstance abusers have particularly high levels of impulsivity and sensation seeking (Conway et al., 2003). In most of the prevailing personality models, one main dimension is novelty seeking or impulsivity or extraversion, which are generally referred to as approach-related traits (Munafo et al., 2008). Novelty seeking is measured using the Tridimensional Personality Questionnaire (TPQ) or the Temperament and Character Inventory (TCI). Extraversion is one of the main dimensions of the Neuroticism Extraversion Openness (NEO) Personality Inventory and the Eysenck Personality Inventory or Questionnaire (EPI or EPQ). Where as the Karolinska Scales of Personality (KSP) has an impulsivity scale. Association studies typically use only one questionnaire, however, dimensions measuring the same construct are highly correlated. Therefore, comparison of genetic findings is possible with the assumption that all of these interrelated traits reflect a common underlying neurobiological motivational mechanism. Because the psychobiological model of TPQ/TCI provides a well-established theoretical framework for an association between the dopamine system and novelty seeking temperament dimension (Cloninger et al., 1993), the original novelty seeking scores or transformed scores from other impulsivity scales are usually reported in dopaminergic genetic association studies.
A substantial genetic component of personality traits has been demonstrated in twin and adoption studies. For example, a large Australian twin study reported heritability for TCI temperament scales that ranged from 30% to 40% (Gillespie et al., 2003). To investigate the specific genetic factors, several candidate gene studies have been conducted, initiated by the groundbreaking association of novelty seeking and the DRD4 7-repeat (or long) allele (Benjamin et al., 1996; Ebstein et al., 1996). Studies aiming to replicate this association resulted in contradictory findings, probably because the indicated genetic factor has a small or modest effect size (Ebstein et al., 2000). Therefore, increasing the size of the studied population and/or utilizing published results for meta-analyses may help to settle the contradictions. Based on a recent meta-analysis, the DRD4 VNTR does not seem to have a significant effect on novelty seeking, whereas the −521 C/T (rs1800955) SNP probably affects this trait (Munafo et al., 2008). The DRD4 −521 T-allele carriers had lower scores on approach-related trait scales; interestingly, a significant association could be observed for novelty seeking (TCI/TPQ) and impulsivity (KSP) but not for extraversion (NEO or EPI/EPQ). This finding leads to questioning the basic assumption that these traits assess the same neurobiological mechanism. An early meta-analysis of the other dopaminergic polymorphisms did not show any significant effect for DRD2 or DAT1 polymorphisms, only the DRD3 Ser9Gly SNP was associated with approach-related traits (Munafo et al., 2003). It is important to mention that the social environment might have a significant and possibly interacting effect. In a longitudinal study, for example, higher novelty seeking scores in the DRD2 A1-allele carriers were observed only if participants had a negative, punitive environment in childhood, and the DRD2 genotype had no effect under more favorable conditions (Keltikangas-Järvinen et al., 2009).
There are only a few MAOA and COMT related studies, and their meta-analyses have not yet been carried out. Interesting findings have been reported in regard to the COMT Val158Met polymorphism. A three-way interaction was observed between COMT, DRD4, and the serotonin transporter polymorphism (5-HTTLPR) on novelty seeking. In the absence of the short 5-HTTLPR allele together with the presence of the high-activity Val/Val COMT genotype, the novelty seeking scores were higher in the DRD4 7+ individuals in two independent populations (Benjamin et al., 2000; Strobel et al., 2003). In terms of solely the COMT genetic effect, the results are not in agreement with one another. The low-activity Met/Met genotype was associated with a high level of novelty seeking (Golimbet et al., 2007), whereas the high-activity Val/Val homozygotes were reported to have higher extraversion scores (Reuter and Hennig, 2005).
A number of studies assessed personality traits as part of the genetic investigations of substance use disorders. For example, higher novelty seeking score was associated with the DRD4 7-repeat allele among heavy-drinking college students (Ray et al., 2009) and in adolescent boys from a high-risk community sample (Laucht et al., 2007). In addition, two preliminary studies were conducted among methamphetamine dependents. Consistent with previous findings on drug users, methamphetamine users had higher novelty seeking scores than controls in both samples. Within the patient groups, a subgroup of the DRD2 A1-allele carriers (Han et al., 2008) or COMT Met-allele carriers (Hosak et al., 2006) had the highest novelty seeking scores. The COMT genetic finding was supported in opiate dependence by our laboratory. We reported increased novelty seeking scores in the presence of the Met-allele among 117 heroin-dependent subjects that participated in a methadone substitution program (Demetrovics et al., 2010).
The self-report questionnaires have strong limitations in measuring human personality dimensions. To better understand the genetic underpinnings of personality, novel and complex experimental paradigms are suggested for further studies, such as broader personality phenotypes (e.g., altruism and pro-social behavior) or objectively measurable endophenotypes from neurophysiological tests (e.g., event-related potentials and prepulse inhibition) or from computer games (Ebstein, 2006). The latter approach has been successfully applied recently for testing a reward-related endophenotype by the Iowa Gambling Task. The DRD4 long allele carriers had higher novelty seeking scores and showed elevated levels of risk-taking behavior (Roussos et al., 2009). Also, emotional processes were assessed in a subset of subjects by startle reactivity. The DRD4 long allele was associated with constricted emotional responses. Another gambling test study measuring event-related potentials did not report a DRD4 −521 C/T SNP effect (unfortunately, the analysis of the DRD4 VNTR was not reported) but showed an increased amplitude of the medial frontal negativity (a larger difference between the gain and loss conditions) in COMT Val/Val homozygotes compared to Met/Met homozygotes. The Val/Val group also exhibited greater beta activity during gain trials compared to the Met/Met group (Marco-Pallares et al., 2009). If these genetic findings are replicated, the objective phenotypes that characterize risk-taking behaviors could be helpful in genetic association studies and diagnostic processes. Animal models for risk-taking behaviors are numerous, and they would be useful to elucidate the underlying neurobiological mechanisms of impulsive decision-making. Adolescent rats, like their human counterparts, exhibit increased risk-taking and novelty seeking behaviors and drug use (Laviola et al., 2003). Therefore, animal studies can be used to assess this vulnerable period of development.
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CONCLUSIONS
We would like to emphasize that genetic association studies do not aim to find good or bad gene variants. Identifying the genetic factors in the background of heritable disorders can help us to better understand the underlying neural mechanisms of the disorder and the related behaviors (e.g., ADHD and impulsive behaviors). Psychiatric disorders can be seen as extremes of certain behaviors. In many cases, a small portion of these extreme behaviors are evolutionarily beneficial in human populations, because they maintain diversity. For example, impulsive risk-taking behavior in a minority of the population can aid survival (Williams and Taylor, 2006). Therefore, gene variants that have been indicated as risk factors in certain psychiatric disorders might have favorable effects under special circumstances.
Since single genetic factors have only small effects on complex inheritance disorders and traits, refining the studied phenotype is necessary. Although heterogeneous disorder categories have been continually replaced by quantitative trait measures in psychiatric genetic studies during the last decade, current parent-rated symptom scales and self-report questionnaires still do not provide the best phenotypes. Objectively measured endophenotypes, such as event-related potentials, fMRI signals that mirror regional brain activity, reaction time measures, or error rates on standardized computerized neurocognitive tests would help us to decipher specific genetic effects. Based on the presented dopaminergic genetic data (summarized in Table 1), we can conclude that dopamine D2 receptors in the subcortical brain regions may be important in reward-related associative learning and behavioral inhibition, as DRD2 gene variants resulting in reduced expression (A1-, B1-, and 957 C-allele) are repeatedly linked to substance abuse and impulsive phenotypes. The widely investigated DRD4 exon 3 VNTR has an influence on PFC-related executive functioning; however, recent results also point out the importance of DRD4 promoter variants. The COMT Val158Met SNP affects cognitive functions by influencing cortical dopamine level. This polymorphism is likely the best example of the good vs. the bad effect of a specific gene variant. The approximate 5050% frequency of the Val- and Met-alleles of this functional polymorphism shows that both variants can have advantageous effects. It has been proposed that the Val-variant is associated with better cognitive flexibility, whereas the Met-variant has been reported to lead to an advantage on memory and attention tasks which require stability (Bilder et al., 2004). The dopamine transporter is a key component of dopamine transmission in the basal ganglia, and therefore, it is important in inhibitory control. However, specific DAT1 gene variants with convincing functional effects have not yet been confirmed. The low-activity allele of the MAOA uVNTR has been shown to be related to aggressive traits. This association could be explained by dopaminergic or serotonergic pathways because this enzyme converts monoamines (dopamine, norepinephrine, and serotonin). The MAOA effect shows the importance of gene × environment interactions. As it can be noticed in recent review papers (Grisham et al., 2008; Nigg et al., 2010), the environmental factors which have been convincingly replicated as risk factors in childhood-onset psychiatric disorders, such as low birth weight and physical or sexual abuse, are not specific to these disorders. Finding specific genetic factors that make individuals vulnerable or resilient to harmful environmental factors is the prevailing approach in present psychiatric genetic research. It is important to note that newer hypotheses refer to the MAOA uVNTR and to the other most commonly researched dopaminergic and serotonergic polymorphisms, i.e., the DRD4 VNTR and the 5-HTTLPR, as plasticity and not vulnerability factors, arguing that the indicated gene variants make individuals more sensitive to environmental influences (to both positive and negative influences) (Belsky et al., 2009). Early adverse environments might exert their effects via epigenetic modulations (Meaney, 2010), which should be taken into account when trying to understand the biological processes leading to disorders and maladaptive behaviors. Longitudinal population-based studies collecting environmental data and animal studies controlling for specific environmental factors would help shed light on the important steps in the development of psychopathologies.
Table 1
Dopaminergic genetic risk factors of psychiatric disorders and related traits.
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Highlights
description of functional polymorphisms in the dopaminergic genes
dopaminergic genetic findings of psychiatric disorders in adolescence, e.g., ADHD
genetic findings of quantitative traits, like impulsive and externalizing behaviors
genetic findings of objective endophenotypes, like attentional performance
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Acknowledgments
This work was supported by the NIH R03 TW007656 Fogarty International Research grant awarded to Maria Sasvari-Szekely and by the Hungarian fund OTKA F67784, awarded to Zsofia Nemoda. We thank Krisztina Lakatos for valuable discussions.
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Footnotes
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