title: Identifying mechanisms that underlie links between COMT genotype and aggression in male adolescents with ADHD.
abstract: BACKGROUND
  There 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.
  
  
  METHODS
  Males 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: School of Psychology, Cardiff University, Cardiff, UK.
authors.forename: Stephanie H M
authors.initials: SH
authors.lastname: van Goozen
authors.affiliation: School of Psychology, Cardiff University, Cardiff, UK.|MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Langley
authors.affiliation: School of Psychology, Cardiff University, Cardiff, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Northover
authors.affiliation: School of Psychology, Cardiff University, Cardiff, UK.
authors.forename: Kelly
authors.initials: K
authors.lastname: Hubble
authors.affiliation: Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.
authors.forename: Katya
authors.initials: K
authors.lastname: Rubia
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.|Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Schepman
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.|Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Michael C
authors.initials: MC
authors.lastname: O'Donovan
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.|Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Anita
authors.initials: A
authors.lastname: Thapar
mesh_terms: D000293:Adolescent; D000374:Aggression / Q000502:physiology*; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D002648:Child; D004644:Emotions / Q000502:physiology*; D004645:Empathy / Q000502:physiology*; D056344:Executive Function / Q000502:physiology*; D005239:Fear / Q000502:physiology*; D005838:Genotype; D006801:Humans; D007266:Inhibition, Psychological; D008297:Male
chemical_list: C588010:COMT protein, human; D002394:Catechol O-Methyltransferase
keywords: ADHD; COMT; aggression; child; conduct disorder; genetic