A Replicated Molecular Genetic Basis for Subtyping Antisocial Behavior in Children With Attention-Deficit/Hyperactivity Disorder

Caspi, Avshalom; Langley, Kate; Milne, Barry; Moffitt, Terrie E.; O'Donovan, Michael Conlon; Owen, Michael John; Tomás, Mónica Polo; Poulton, Richie; Rutter, Michael; Taylor, Alan; Williams, Benjamin; Thapar, Anita

doi:10.1001/archgenpsychiatry.2007.24

Cited by 196 publications

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References 49 publications

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“…The findings not only suggest it is emotional processes rather than executive dysfunction that mediate links between genotype and aggression but also more specifically that these involve differences at a physiological level as well as in terms of reported experiences and appear to be specific to the emotion of fear. In the previous cohort study (Langley et al., 2010), and in a meta‐analysis (Caspi et al., 2008) COMT Val158Met predicted antisocial behaviour in those with ADHD. Here, although we observed genetic association with performance on three different types of neuropsychological/physiological task, no direct association with aggression was observed.…”

Section: Discussionmentioning

confidence: 93%

“…Links with aggression were indirectly mediated. COMT Val158Met has been observed to predict aggression/extreme antisocial behaviour in individuals with ADHD (Caspi et al., 2008; Langley et al., 2010; Monuteaux et al., 2009; Salatino‐Oliveira et al., 2012) across six independent studies and in a meta‐analysis (Caspi et al., 2008) with the association applying to the subtype of aggression in those with ADHD, not to aggressive behaviour in the general population (Caspi et al., 2008). Given the small effect size of COMT Val158Met observed in the original studies and meta‐analysis, the most plausible reason for failing to observe a direct effect in this subsample is that the sample size was too small.…”

Section: Discussionmentioning

confidence: 99%

“…However, we were still able to demonstrate indirect effects of genotype via reduced fear conditioning and fear empathy on aggression in ADHD using mediation analysis. As our hypothesis involved ADHD patients only [ COMT Val158Met does not predict aggression in the general population (Caspi et al., 2008)], for the present investigation we did not examine healthy controls. Future studies will be required to further examine healthy adolescents and the development of aggression in other populations and to replicate these findings.…”

Section: Discussionmentioning

confidence: 99%

“…It is a gene variant that has been very well researched in human and animal studies. Meta‐analyses show that COMT Val158Met has pleiotropic effects on both executive function and emotional measures (Mier, Kirsch, & Meyer‐Lindenberg, 2009), processes that are important in relation to aggression, as well as effects on antisocial behaviour in those with ADHD (Caspi et al., 2008). Studies reveal worse performance on cognitive tasks assessing executive function in high‐activity Val allele carriers (Barnett et al., 2007; Langley, Heron, O'Donovan, Owen, & Thapar, 2010; Tunbridge, Harrison, & Weinberger, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…In keeping with findings from previous pooled analyses (Caspi et al., 2008; Mier et al., 2009), this gene variant was found to predict three phenotypes: a task assessing executive control, a questionnaire measure of social/emotion function and aggression/antisocial behaviour in children with higher ADHD scores. However, the questionnaire measure of social/emotional function rather than executive control appeared to partially mediate the link between COMT genotype and aggression/antisocial behaviour in children with higher ADHD scores (see Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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Identifying mechanisms that underlie links between COMT genotype and aggression in male adolescents with ADHD

Goozen

Langley

Northover

et al. 2015

Child Psychology Psychiatry

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BackgroundThere is a known strong genetic contribution to aggression in those with ADHD. In a previous investigation of a large population cohort, impaired ‘emotional/social cognitive’ processing, assessed by questionnaire, was observed to mediate the link between COMT Val158Met and aggression in individuals with ADHD. We set out to replicate and extend this finding in a clinical sample, using task‐based and physiological assessments of emotional and cognitive processing. Our aim was to test the hypothesis that directly assessed emotional processing mediates the link between COMT Val158Met and aggression in young people with ADHD.MethodsMales aged 10–17 years with ADHD were recruited from UK community clinics (n = 194). Research diagnostic interviews (parent and child) were used to assess psychopathology and generate DSM‐IV Conduct Disorder symptom scores. Participants completed tasks assessing executive function (response inhibition and set shifting), empathy for fear, sadness and happiness, and fear conditioning [measured using skin conductance responses (SCR) to aversive stimuli].Results COMT Val allele carriers showed poorer response inhibition (F = 5.27, p = .02) and set shifting abilities (F = 6.45, p = .01), reduced fear empathy (F = 4.33, p = .04) and reduced autonomic responsiveness (lower SCRs) to the conditioned aversive stimulus (F = 11.74, p = .001). COMT Val158Met did not predict impairments in recognising others' emotions or affective empathy for happiness or sadness. Mediation analysis revealed that impaired fear‐related mechanisms indirectly mediated the link between COMT Val158Met and aggression.ConclusionOur findings suggest fear mechanisms as possible targets for psychological interventions to disrupt links between genetic risk and aggressive outcomes in ADHD. Our findings also reveal the potential of hypothesis‐driven approaches for identifying neuropsychological mechanisms that mediate genetic risk effects on behaviour and psychopathology.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Identifying mechanisms that underlie links between COMT genotype and aggression in male adolescents with ADHD

Goozen

Langley

Northover

et al. 2015

Child Psychology Psychiatry

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Genotype Link With Extreme Antisocial Behavior

Langley

Heron²,

O'Donovan³

et al. 2010

Arch Gen Psychiatry

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The high-activity COMT genotype in ADHD is associated with antisocial behavior in part via impaired social understanding. Impaired executive control was also associated with the high-activity COMT genotype but may not lie on the risk pathway to antisocial behavior. The findings demonstrate the importance of testing links between genotype, intermediate phenotype, and clinical outcome in the same sample to identify potential risk pathways.

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Gene × Disease Interaction on Orbitofrontal Gray Matter in Cocaine Addiction

Alia‐Klein¹,

Parvaz²,

Woicik³

et al. 2011

Arch Gen Psychiatry

101

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Context Chronic cocaine use has been associated with structural deficits in brain regions having dopamine receptive neurons. However, the concomitant use of other drugs and common genetic variability in monoamine regulation present additional structural variability. Objective To examine variations in gray matter volume (GMV) as a function of lifetime drug use and the monoamine oxidase A (MAOA) genotype in men with cocaine use disorders (CUD) and healthy male controls. Design Cross-sectional comparison between 40 CUD and 42 controls scanned with magnetic resonance imaging (MRI) to assess GMV and genotyped for the MAOA polymorphism. The impact of cocaine addiction on GM was tested by 1) comparing CUD with controls, 2) testing diagnosis-by-MAOA interactions, and 3) correlating GMV with lifetime cocaine, alcohol, and cigarette smoking, and testing their unique contribution to GM beyond other factors. Outcome Measures GMV were derived from MRI with voxel-based-morphometry. Genotyping was performed for a functional polymorphism (a variable number tandem repeat or VNTR) in the promoter region of the MAOA gene with “high” and “low” alleles. Results 1) Individuals with CUD had reductions in GMV in the orbitofrontal (OFC), dorsolateral prefrontal (DLPFC) and temporal cortex, and hippocampus, compared to controls. 2) The OFC reductions were uniquely driven by CUD with low MAOA genotype and by lifetime cocaine use. 3) GMV in the DLPFC and hippocampus, was driven by lifetime alcohol use beyond the genotype and other pertinent variables. Conclusions This study documents for the first time, the enhanced sensitivity of CUD low MAOA carriers to GM loss, specifically in the OFC, indicating that this genotype may exacerbate the deleterious effects of cocaine in the brain. In addition, chronic alcohol use was a major contributor to GM loss in the DLPFC and hippocampus, and is likely to further impair executive function and learning in cocaine addiction.

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A Replicated Molecular Genetic Basis for Subtyping Antisocial Behavior in Children With Attention-Deficit/Hyperactivity Disorder

Abstract: The findings confirm the presence of genetic heterogeneity in ADHD and illustrate how genetic information may provide biological evidence pointing to clinical subtypes.

Cited by 196 publications

References 49 publications

Identifying mechanisms that underlie links between COMT genotype and aggression in male adolescents with ADHD

Identifying mechanisms that underlie links between COMT genotype and aggression in male adolescents with ADHD

Genotype Link With Extreme Antisocial Behavior

Gene × Disease Interaction on Orbitofrontal Gray Matter in Cocaine Addiction

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