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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 V al 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. Conclusion 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. [ABSTRACT FROM AUTHOR]

Background The genetic architecture of ADHD is complex, with rare and common variants involved. Common genetic variants (as indexed by a composite risk score) associated with clinical ADHD significantly predict ADHD and autistic-like behavioural traits in children from the general population, suggesting that ADHD lies at the extreme of normal trait variation. ADHD and other neurodevelopmental disorders share neurocognitive difficulties in several domains (e.g. impaired cognitive ability and executive functions). We hypothesised that ADHD composite genetic risk scores derived from clinical ADHD cases would also contribute to variation in neurocognitive abilities in the general population. Methods Children ( N = 6,832) from a UK population cohort, the Avon Longitudinal Study of Parents and Children ( ALSPAC), underwent neurocognitive testing. Parent-reported measures of their children's ADHD and autistic-like traits were used to construct a behavioural latent variable of 'neurodevelopmental traits'. Composite genetic risk scores for ADHD were calculated for ALSPAC children based on findings from an independent ADHD case-control genome-wide association study. Structural equation modelling was used to assess associations between ADHD composite genetic risk scores and IQ, working memory, inhibitory control and facial emotion recognition, as well as the latent 'neurodevelopmental trait' measure. Results The results confirmed that neurocognitive and neurodevelopmental traits are correlated in children in the general population. Composite genetic risk scores for ADHD were independently associated with lower IQ ( β = −.05, p < .001) and working memory performance ( β = −.034, p = .013), even after accounting for the relationship with latent neurodevelopmental behavioural trait scores. No associations were found between composite genetic risk scores and inhibitory control or emotion recognition ( p > .05). Conclusions These findings suggest that common genetic variants relevant to clinically diagnosed ADHD have pleiotropic effects on neurocognitive traits as well as behavioural dimensions in the general population. This further suggests that the well-recognised association between cognition and neurodevelopmental behavioural traits is underpinned at a biological level. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia is a neurodevelopmental disorder, and risk genes are thought to act through disruption of brain development. Several genetic studies have identified dystrobrevin-binding protein 1 (DTNBP1, also known as dysbindin) as a potential susceptibility gene for schizophrenia, but its impact on brain development is poorly understood. The present investigation examined for the first time the effects of DTNBP1 on brain structure in children. Our hypothesis was that a genetic variation in DTNBP1 (i.e., the single nucleotide polymorphism rs2619538) would be associated with differences in both gray and white matter brain regions previously implicated in schizophrenia. Methods: Magnetic resonance imaging and voxel-based morphometry were used to examine brain structure in 52 male children aged between 10 and 12 years. Statistical inferences on the effects of DTNBP1 genotype on gray and white matter volume (GMV and WMV) were made at p < .05 after family-wise error correction for multiple comparisons across the whole brain. Results: Individuals homozygous for the schizophrenia high-risk allele (AA) compared with those homozygous for the low-risk allele (TT) expressed reduced GMV in the left anterior cingulate gyrus and reduced WMV in the left medial frontal area. Conclusions: Our results suggest that genetic variation in DTNBP1 is associated with differences in gray and white matter; and that these effects are already evident in children as young as 10-12 years. These findings are consistent with the notion that the DTNBP1 genotype influences brain development and may thereby modulate vulnerability to schizophrenia. [ABSTRACT FROM AUTHOR]