Catechol O-Methyltransferase Gene Variant and Birth Weight Predict Early-Onset Antisocial Behavior in Children With Attention-Deficit/Hyperactivity Disorder

Department of Psychological Medicine, College of Medicine, School of Psychology, Cardiff University, Heath Park, Cardiff, Wales.
Archives of General Psychiatry (Impact Factor: 14.48). 12/2005; 62(11):1275-8. DOI: 10.1001/archpsyc.62.11.1275
Source: PubMed


Early-onset antisocial behavior accompanied by attention-deficit/hyperactivity disorder is a clinically severe variant of antisocial behavior that is associated with a particularly poor outcome. Identifying early predictors is thus important. Genetic and prenatal environmental risk factors and prefrontal cortical function are thought to contribute. Recent evidence suggests that prefrontal cortical function is influenced by a valine/methionine variant in the catechol O-methyltransferase (COMT) gene.
To test the a priori hypothesis that this genetic variant predicts early-onset antisocial behavior in a high-risk sample and further examine the effects of birth weight, an environmentally influenced index of prenatal adversity previously linked to childhood disruptive behaviors and genotype x birth weight interaction.
A family-based genetic study was undertaken between 1997 and 2003. Participants were prospectively recruited from child and adolescent psychiatry and child health clinics in the United Kingdom and included 240 clinic children who met diagnostic criteria for attention-deficit/hyperactivity disorder or hyperkinetic disorder. Participants underwent comprehensive standardized assessments including measures of antisocial behavior and IQ. Main Outcome Measure DSM-IV symptoms of childhood-onset conduct disorder rated by trained interviewers using a standard diagnostic interview.
The results show main effects of the COMT gene variant (P = .002), birth weight (P = .002), and a significant gene x environment (COMT x birth weight) interaction (P = .006).
Early-onset antisocial behavior in a high-risk clinical group is predicted by a specific COMT gene variant previously linked with prefrontal cortical function and birth weight, and those possessing the val/val genotype are more susceptible to the adverse effects of prenatal risk as indexed by lower birth weight.

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    • "Studies on the genetics of ADHD, include genetic linkage studies (Thapar et al., 2007), genome-wide association studies (GWAS) (Franke et al., 2009), and numerous allelic and susceptibility gene association studies. The latter have found positive associations with genes for dopamine (DA) transporter (DAT1) (Genro et al., 2008), DA D4 receptor (DRD4) (Kustanovich et al., 2004), and catechol-O-methyltransferase (COMT) (Thapar et al., 2005). However, other studies have not replicated these findings (Gizer et al., 2009; Kustanovich et al., 2004). "
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    • "However, some associated factors also appear to be unique to conduct disorder in ADHD. Notably, the functional COMT Val158Met variant has been found to be associated with conduct problems in ADHD (40), a finding that has been replicated in six independent samples (32, 41–43), while meta-analysis shows that this variant is not associated with ADHD risk (44). A separate issue of interest would be to investigate the independent contribution of genetic liability associated with conduct disorder (regardless of ADHD). "
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    ABSTRACT: Objective Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. Method Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. Results Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items. Conclusions Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.
    American Journal of Psychiatry 04/2013; 170(8). DOI:10.1176/appi.ajp.2013.12081129 · 12.30 Impact Factor
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    • "However, the literature on disruptive disorders suggests that there may also be birth weight by genotype interactions in play (Buschgens et al., 2009). Specifically, an interaction between birth weight and dopamine genes (COMT, DAT1, DRD5) has been suggested to affect co-morbid oppositional symptoms in ADHD (Langley et al., 2007; Thapar et al., 2005). Thus, there is evidence for both independent and interactive effects of candidate genes and birth weight in ADHD. "
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    ABSTRACT: This study investigates the effects of XKR4, a recently identified candidate gene for Attention-Deficit/Hyperactivity Disorder (ADHD), birth weight, and their interaction on brain volume in ADHD. XKR4 is expressed in cerebellum and low birth weight has been associated both with changes in cerebellum and with ADHD, probably due to its relation with prenatal adversity. Anatomical MRI scans were acquired in 58 children with ADHD and 64 typically developing controls and processed to obtain volumes of cerebrum, cerebellum and gray and white matter in each structure. DNA was collected from saliva. Analyses including data on birth weight were conducted in a subset of 37 children with ADHD and 51 controls where these data were retrospectively collected using questionnaires. There was an interaction between genotype and birth weight for cerebellum gray matter volume (p = .020). The combination of homozygosity for the G-allele (the allele previously found to be overtransmitted in ADHD) and higher birth weight was associated with smaller volume. Furthermore, birth weight was positively associated with cerebellar white matter volume in controls, but not ADHD (interaction: p = .021). The interaction of genotype with birth weight affecting cerebellum gray matter is consistent with models that emphasize increased influence of genetic risk-factors in an otherwise favorable prenatal environment. The absence of an association between birth weight and cerebellum white matter volume in ADHD suggests that other genetic or environmental effects may be at play, unrelated to XKR4. These results underscore the importance of considering environmental effects in imaging genetics studies.
    Clinical neuroimaging 12/2012; 2(1):103-10. DOI:10.1016/j.nicl.2012.11.010 · 2.53 Impact Factor
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