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: 13.75). 12/2005; 62(11):1275-8. DOI: 10.1001/archpsyc.62.11.1275
Source: PubMed

ABSTRACT 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, 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.
    12/2012; 2:103-10. DOI:10.1016/j.nicl.2012.11.010
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    • "In addition, Qian et al. [2003] and Biederman et al. [2008] suggested that the methionine allele conferred risk to ADHD in boys, whereas the valine allele conferred risk to ADHD in girls. In the neurophysiological studies, valine/ methionine polymorphism is found associated with antisocial and aggressive behaviors of ADHD [Thapar et al., 2005; Caspi et al., 2008]. The current meta-analysis of val/met SNP (rs4680) association with childhood ADHD has not indicated any association with any evidence for heterogeneity (Table I) [Gizer et al., 2009]. "
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    ABSTRACT: Attention deficit/hyperactivity disorder (ADHD) in children is a neurobehavioral disorder characterized by inattention, hyperactivity, and/or impulsivity. The biochemical abnormalities and genetic factors play significant roles in the etiology of ADHD. These symptoms affect the behavior performance and social relationships of children in school and at home. Recently, many studies about biochemical abnormalities in ADHD have been published. Several research groups have also suggested the genetic contribution to ADHD, and attempted to identify susceptibility and candidate genes for this disorder through the genetic linkage and association studies. To date, these studies have reported substantial evidence implicating several genes (dopaminergic: DRD4, DAT1, DRD5, COMT; noradrenergic: DBH, ADRA2A; serotonergic: 5-HTT, HTR1B, HTR2A; cholinergic: CHRNA4, and central nervous system development pathway: SNAP25, BDNF) in the etiology of ADHD. Understanding the biochemistry and genetics of ADHD will allow us to provide a useful addition with other treatment procedures for ADHD.
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