ARTICLES
COMT Val108/158Met Gene Variant, Birth Weight, and Conduct Disorder in Children With ADHD

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ABSTRACT

Objective

In a recent study, Thapar and colleagues reported that COMT “gene variant and birth weight predict early-onset antisocial behavior in children” with attention-deficit/hyperactivity disorder. We have attempted to replicate these findings in a group of ADHD children using a similar research design.

Method

Children (n = 191) between 6 and 12 years of age who were diagnosed with ADHD were included in the study. Conduct disorder was diagnosed according to DSM-IV criteria based on clinical evaluation and a structured interview (Diagnostic Interview Schedule for Children-IV). The mother's report on the child's birth weight was used in the analysis. Logistic regression analysis, with genotype and birth weight as independent variables and DSM-IV conduct disorder as the dependent variable, was conducted.

Results

No significant main effects of genotype and birth weight or interaction effects on conduct disorder were observed.

Conclusion

In this sample of children diagnosed with ADHD, we find no association between the COMT Val108/158Met gene variant, birth weight, and conduct disorder. Further investigations are required before using birth weight and COMT genotype as predictors of conduct disorder in children with attention-deficit/hyperactivity disorder, especially given the societal and legal ramifications of conduct disorder.

Section snippets

Subjects

One hundred ninety-one children (167 boys, 24 girls), between 6 and 12 years old with a mean age of 9 years (SD = 1.8), were recruited from the Disruptive Behavior Disorders Program and the child psychiatry outpatient clinics at the Douglas Hospital in Montreal. They were referred to these specialized care facilities by schools, community social workers, family doctors, and pediatricians. Details about diagnostic procedures have been described elsewhere (Grizenko et al., 2006). Briefly, every

Demographic and Clinical Characteristics of Sample

The ethnicity of the subjects (n = 191) included in the study were as follows: 90.1% white, 4.2% black, 1.6% aboriginal, 3.6% half-white, and.5% half-Asian. In terms of family income, 38.9%, 26.6%, and 34.4% of the children in the study were from families with an income less than Can$20,000/year (low income), between Can$20,000 and $40,000/year (lower middle income), and more than Can$40,000/year, respectively. Fathers of the assessed children had a mean of 12 years of education (SD = 3.2) and

DISCUSSION

In this study with ADHD children (N = 191), we were unable to replicate the results obtained by Thapar and colleagues, even though we used a similar design. Several explanations may be invoked for this discrepancy. The first question is whether our study has sufficient statistical power to detect an effect because our sample was smaller than that used by Thapar and colleagues (N = 240). Based on the value of the regression coefficient in the original study (R = 0.33; A. Thapar, personal

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      Interestingly, the majority of these studies focused on prenatal adversity, with the Val/Val genotype exhibiting increased CD symptoms and aggression in the presence of low birth weight (Thapar et al., 2005) and prenatal maternal smoking (Brennan et al., 2011). In contrast, Sengupta et al. (2006) were unable to observe an interaction between COMT and birth weight in relation to CD. Notably, these authors investigated an ADHD sample of mixed ethnicity, which might account for the divergent results.

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      Taken together, these findings suggest that the combination of the Val/Val genotype and prenatal exposure to maternal smoking may lead to neural processing deficits that increase vulnerability for aggression and ADHD in adolescence and adulthood. One previous study examining the interaction of prenatal risk and COMT variation in the prediction of externalizing problems found that birth weight interacted with Val108/158Met to predict antisocial behavior in an ADHD sample (Thapar et al., 2005); however, this finding has had at least one failure to replicate (Sengupta et al., 2006). Although Thapar et al. (2005) stated that Val108/158Met did not interact with maternal prenatal smoking to predict antisocial behavior in their sample, specific methodological details (e.g., how maternal smoking was measured) are unclear.

    • Perinatal risk factors in the development of aggression and violence

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      Taken together, these findings suggest that the combination of the Val/Val genotype and prenatal exposure to maternal smoking may lead to neural processing deficits that increase vulnerability for aggression. One study examining the interaction of prenatal risk and COMT variation in the prediction of antisocial outcomes found that birth weight interacted with Val108/158Met to predict antisocial behavior in an ADHD sample (Thapar et al., 2005); however, this finding has had at least one failure to replicate (Sengupta et al., 2006). Another recent study (Brennan et al., 2011) found that individuals with the COMT Val/Val genotype whose mothers also smoked during pregnancy were at an increased risk for aggressive behavior outcomes in adolescence and young adulthood.

    • Fetal origins of mental health: Evidence and mechanisms

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      For example, men (but not women) with the A2/A2 variant of the Taq1A polymorphism in the dopamine receptor D2 (DRD2) gene did not show a negative effect of fetal growth on educational attainment later in life (Keltikangas-Jarvinen et al., 2007). In a study on psychopathology, participants with the val/val variant of a polymorphism in the catechol-O-methyltransferase (COMT) gene were more susceptible to effects of prenatal adversity on postnatal antisocial behaviour (Thapar et al., 2005), while another study failed to replicate this finding (Sengupta et al., 2006). Another study found that maternal smoking during pregnancy and birth weight interacted with polymorphisms in the dopamine receptor D5 (DRD5) and the dopamine transporter (DAT1) genes in affecting antisocial behaviour of the offspring later in life (Langley et al., 2008).

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    This work was supported in part by a grant from the Fonds de la Recherche en Santé du Québec and the Canadian Institutes of Health Research to R.J. and N.G. and a grant from the Sackler Foundation. The authors thank Sandra Robinson, Sharon Hill, and Nicole Pawliuk for technical and clinical assistance.

    Disclosure: Dr. Joober has served as a consultant for Janssen-Ortho, Canada, since May 2006. The other authors have no financial relationships to disclose.

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