The relation of ADHD and violent aggression: What can we learn from epidemiological and genetic studies?

Abstract

Disruptive behavior includes psychopathological and behavioral constructs like aggression, impulsivity, violence, antisociality and psychopathy and is often closely related with diagnostic categories like conduct disorder (CD), attention deficit disorder (ADHD) and antisocial personality disorder (ASP). There is now clear evidence that neurobiological and environmental factors contribute to these phenotypes. A mounting body of evidence also suggests interactive effects of genetic and environmental risks.

In this selective review we give an overview over epidemiological aspects of the relation between ADHD and antisocial behavior, including violent aggression and psychopathy. Moreover, we summarize recent findings from molecular genetic studies and particularly discuss pleiotropic effects of a functional polymorphism of the serotonin transporter promoter gene (5HTTLPR) and childhood adversity on ADHD and violent behavior. The reported gene–environment interactions are not only informative for understanding the neurobiological underpinnings of disruptive behavior, but also throw some light on the relation between ADHD and violent behavior from a genetic perspective. The impact of genetic research on forensic psychiatry and future directions of neurobiological research are discussed.

Introduction

Social maladaptive, disruptive behavior arises from several conditions including genetic disposition as well as cultural and social factors, which are enforced on the background of the individual's experiences (Fig. 1). Important progress has been made in identifying genetic risk factors that predispose to antisocial behavior (Raine, 1993, Volavka, 2002). Also much progress has been made in uncovering psychosocial risk factors for antisocial and violent behavior (Farrington, 2000, McCord, 2001). The discussion in the past regarding the role of “nature” and “nurture” has been now followed by research on interaction between genetic and environmental influences on the development of disruptive behavior (Raine, 2002).

Beside research on the influence of genes and environment with disruptive behavior, investigations concerning the association with psychiatric disorders provide an additional source to elucidate the neurobiological and environmental underpinnings of aggression, violence and antisociality. Among other psychiatric disorders like schizophrenia, suicidal depression and cluster B personality disorders, attention deficit/hyperactivity disorder (ADHD) is of particular interest in this context, because it is characterized by psychopathological complex of attentional problems, motor overactivity and impulsivity, which is per se closely linked to behavioral problems. In addition, this disorder starts early in life and, therefore, is suggested to have high impact of an individual's socialization.

In this report we summarize some work concerning genetic influences on ADHD and violent behavior with a focus on genes involved in the regulation of serotonergic neurotransmission. This work also turns towards the question of gene–environment interactions in the etiology of ADHD and violent aggression and sheds some light on the relation of violence and ADHD from a genetic perspective.

Despite the heterogeneity of definitions and classifications used and the difficulties regarding operationalization and assessment of antisocial behavior phenotypes, there is clear evidence from twin, adoption and molecular genetic studies to support the notion that there are genetic influences on antisocial and aggressive behavior (Raine, 1993). It has to be emphasized that the variability of findings regarding the magnitude of environmental and genetic contribution is high. This variability is not only attributable to differences between the investigated populations, but also to the difficulties in the measurement of disruptive disorders or antisocial behavior. The composition of well observable behavioral (e.g. violence, verbal aggression) and psychopathological features (e.g. unemotionality, hostility) differs profoundly between the investigated phenotypes. Moreover, there is often a fluent passage between phenotypes which should be delineated. For instance, an aggressive act might present features of proactive and reactive aggression that might provide problems regarding unequivocal classification.

In a meta-analysis of 51 twin and adoption studies Rhee and Waldman (2002) estimated moderate genetic (additive 32%, non-additive 9%) and environmental influences (shared 16%, non-shared 43%) on antisocial behavior. More specifically, moderate heritability has been also found for violent behavior (Cloninger and Gottesman, 1987, Rushton, 1996). Twin- and adoption studies also provide information which go beyond pure quantification of genetic and environmental effects. One example is the evaluation of gender differences. It has been shown that the magnitude of environmental and genetic influences on antisocial behavior is equal for males and females (Rhee and Waldman, 2002, Widom and Ames, 1988), but also a slightly higher genetic load in males was found (Miles & Carey, 1997). Given the higher prevalence of antisocial behavior in males than females and the little or absent difference in the magnitude of genetic effect on antisocial behavior, different genes or environmental factors or both might be important within each sex.

Another important issue are developmental changes of the genetic and environmental impact on antisocial behavior phenotypes. Although Rhee and Waldman (2002) found a decrease of familial genetic and environmental factors and an increase of non-familial factors from childhood to adulthood, the direction of difference regarding heritability varies across studies (DiLalla and Gottesman, 1989, Miles and Carey, 1997). These discrepancies might be partially due to confounding methods of measurement of behavioral phenotypes, but also to various subtypes of individuals with different life-course patterns of antisociality (e.g. life-course persistent vs. adolescence-limited; Moffitt, 2003).

But not only differentiation of developmental subtypes, but also more detailed psychopathological characterization of antisocial behavior reveals additional information from twin- and adoption studies. Examples for this are the finding that continuous aggressive but not non-aggressive antisocial behavior is largely genetically mediated (Eley, Lichtenstein, & Moffitt, 2003) or that antisocial behavior is more heritable in children with than without concomitant callous-unemotional personality traits (Viding, Jones, Frick, Moffitt, & Plomin, 2008). It could also be demonstrated that the importance of genetic and environmental influences varies regarding subgroups of individuals with antisocial behavior, if measures of attention deficit disorder, conduct and oppositional disorder and other psychopathological features were used for latent class analysis (Silberg et al., 1996), suggesting heterogeneity of antisocial behavior and emphasizing the need for multivariate approaches for studying phenotypes related with antisociality.

Further, adoption studies provide substantial evidence that environmental and genetic risks interact. For example in a Swedish study 40% of adoptees were criminal when both genetic and postnatal environmental risks were present, but only 12.1% and 6.7% were criminal in presence of either genetic or environmental risks, respectively (Cloninger, Sigvardsson, Bohman, & von Knorring, 1982). These results suggest a non-additive but interactive effect of genetic and environmental risks for antisocial behavior.

Molecular genetic linkage and association studies have now just begun to reveal the architecture of antisocial behavior more in detail. Results from few linkage studies regarding conduct disorder and antisociality performed so far are not consistent (Dick et al., 2004, Dick et al., 2008, Kendler et al., 2006, Stallings et al., 2005). Association studies have mainly focused on risk genes which are involved in the regulation of monoaminergic neurotransmission. They include catecholaminergic and serotonergic genes, but also genes which have been related to aggressive and violent behavior due to animal models, like the nitric oxide synthase (NOS-I) gene (Reif et al., 2009). For example, dopamine receptor D₂ (DRD2) and dopamine receptor D₄ (DRD4) gene variants and interaction between them are associated with conduct disorder and antisocial behavior (Beaver et al., 2007, Congdon et al., 2008). Also the catechol-o-methyltransferase (COMT) gene has been associated with increased aggressive behavior, at least in several samples of psychiatric patients (Volavka, Bilder, & Nolan, 2004). Most evidence regarding genetic regulation of antisocial behavior has been collected for serotonergic genes and will be outlined below.

Although suggested from epidemiological genetic investigations, the study of gene–environment interactions is still quite new in the field of neuroscience (Caspi & Moffitt, 2006). Several lines of investigations provide increasing evidence that the effect of environmental pathogens on the development of mental disorders or behavioral traits including antisocial behavior is conditional on the individual's genotype. These comprise experiments with animal models, which allow to control both genetic and environmental conditions and studies that compare human genotype groups on their response to environment. Moreover, the use of neuroimaging or neurophysiological techniques allows identifying functional and anatomical networks, which are involved in the response to environmental stimuli in experimental settings. For example, it could be shown that amygdala volume and prefrontal and amygdala activation in response of emotional stimuli is mediated by the MAO-A genotype (Meyer-Lindenberg et al., 2006). Thus, combination of epidemiological genetics with neuroscientific techniques allows progressing insight in the mechanisms of the genetic control of environmental effects in mental disorders or antisocial behavior.