Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis

Mier, Daniela; Kirsch, Peter; Meyer‐Lindenberg, Andreas

doi:10.1038/mp.2009.36

Cited by 419 publications

(472 citation statements)

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“…This has been observed in healthy adults and young people (Langley et al., 2010; Mier et al., 2009), patients with schizophrenia (Tunbridge et al., 2006) and in mice (Papaleo et al., 2008) and extends to male adolescents with ADHD. Specifically Val carriers showed poorer set shifting abilities and response inhibition (measures of executive function), poorer fear‐related empathy and greater failure to condition to an aversive stimulus (CS+) as assessed by skin conductance responses.…”

Section: Discussionmentioning

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%

“…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%

“…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). The Val158Met polymorphism is also associated with performance on paradigms involving emotional arousal and fear processing (Mier et al., 2009; Montag et al., 2008). These findings are remarkably similar in mice (Papaleo et al., 2008).…”

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: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…This includes the study of the development of neurochemical systems, myelinization, grey/white matter growth, synaptic function, etc., as well as the study of the genetic and environmental causes of individual variability. Together with progress in identifying genetic risk factors for psychiatric illness, brain imaging, and brain imaging genetics confer the opportunity to provide mechanistic explanations about how genetic and environmental risk factors may affect neural circuits and cognitive systems, and how this may lead to clinical symptoms [6][7][8].…”

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confidence: 99%

Brain imaging: closing the gap between basic research and clinical application is urgently needed

Buitelaar

Coghill

2013

Eur Child Adolesc Psychiatry

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Brain imaging has revolutionized neural science over the past decades through the identification and description of the neural circuits involved in social cognition, cognitive control, memory, empathy, mood regulation and many other domains. The characterization of these neural circuits at the level of brain structure and function has deepened our understanding of the neural underpinnings of virtually all psychiatric disorders, from ADHD and autism to anxiety and mood disorders, and from schizophrenia to bipolar illness and Alzheimer's disease. One significant newly acquired insight is that psychiatric disorders may be understood best not so much by a neural lesion model focused on discovering specific brain regions where ADHD, autism and other disorders 'reside'. Rather, a disruption of optimal structural and functional connectivity between separate areas of the brain, alongside interference of well-coordinated and synchronized activity of various neural systems turn out to be a most valuable perspective for understanding the biological basis of psychiatric disorders. These may be conceptualized as 'systems disorders of the brain' [1][2][3][4][5]. Brain imaging has also started to add a developmental perspective by outlining how neural circuits develop over age and how this influences and interacts with maturation of cognitive functions and development of behavioral competences. As such, developmental psychopathology has been complemented by developmental neuroscience, i.e. the study of individual patterns of development of the structure and functions of the brain. This includes the study of the development of neurochemical systems, myelinization, grey/white matter growth, synaptic function, etc., as well as the study of the genetic and environmental causes of individual variability. Together with progress in identifying genetic risk factors for psychiatric illness, brain imaging, and brain imaging genetics confer the opportunity to provide mechanistic explanations about how genetic and environmental risk factors may affect neural circuits and cognitive systems, and how this may lead to clinical symptoms [6][7][8].The current issue provides four review papers on brain imaging that are relevant for child and adolescent psychiatry. Johnston et al. [9] discuss the clinical relevance of brain imaging for clinical prediction in psychiatry. In particular, the application of pattern detection technique such as support vector machines has already demonstrated its potential to predict diagnostic status and might further contribute to predictions on treatment response and course of the disorder. Rubia [10] reviews the functional MRI literature on the functional development of cognitive and motivational control, timing, and attention, as well as the development of resting state neural networks. She signals a shift with age from bottom-up processing regions to topdown control in cortico-cortical and cortico-subcortical pathways. Although psychological trauma is a frequent cause of psychopathology at all ages, research into...

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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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Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis

Cited by 419 publications

References 69 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

Brain imaging: closing the gap between basic research and clinical application is urgently needed

Genotype Link With Extreme Antisocial Behavior

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