The three childhood disruptive behavior disorders (DBDs), attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD), are characterized by developmentally extreme and impairing levels of distractibility, hyperactivity, impulsivity, hostility, and aggression . They account for a significant number of child psychiatry referrals . The most common comorbid disorder in ADHD is ODD, with our prior work reporting that 36.5% of children with ADHD have ODD in a sample of Chinese outpatients .
DSM-IV for ADHD describes three subtypes: predominantly inattentive type (ADHD-IA), predominantly hyperactive-impulsive type (ADHD-HI), and combined type (ADHD-C), each with different characteristics and correlates . Although ADHD is characterized by core symptoms (inattention, hyperactivity and impulsivity), there is considerable heterogeneity in clinical features among individuals with ADHD . Some twin studies have demonstrated that the transmission of inattentive and hyperactive-impulsive symptoms is distinct [5, 6]. With a heritability estimate of 0.76 , evidence that the etiology of ADHD is partially due to genes is compelling. The evidence that there may be genes associated with specific ADHD subtypes [6, 8] supported the heterogeneity inherent in the definition of ADHD. Research has found that specific candidate genes are associated with specific subtypes of ADHD in China. In our prior work, the Met allele of COMT was over transmitted to ADHD boys, especially the ADHD-IA subtype, and the -697G allele and haplotype -759C/-697G of HTR2C was significantly over transmitted to ADHD-C probands [9–11].
Because there is evidence that the covariation between ADHD, ODD, and CD is largely due to shared genetic influences [12, 13], it is likely that at least some genes are related to general susceptibility to DBDs , and that dopaminergic genes may influence all of the externalizing disorders.
Monoamine neurotransmitters in the brain, including dopamine (DA), noradrenalin (NE), and serotonin (5-HT), are metabolized by two key enzymes, catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). These two enzymes are of interest in the study of aggressive behavior in both animals and human subjects.
The human COMT gene on 22q11 contains a functional polymorphism (Val158Met) affecting the activity of the enzyme at body temperature [14, 15]. The low-activity Met allele results in slower inactivation of extracellular dopamine within the brain, especially in prefrontal cortex [15, 16]. There are data showing gender-specific effects of COMT Val158Met genetic polymorphism on measures of cognitive function . We have previously reported the low enzyme activity COMT Met allele was preferentially transmitted to ADHD boys but not girls . Early-onset antisocial behavior in a high risk clinical group is predicted by COMT Val158Met and birth weight, in which children with the ValVal genotype were more susceptible to the effects of lower birth weight, had more symptoms of conduct disorder and more aggressive behaviors compared with Met carriers [18, 19], although one study gave negative results .
The gene for monoamine oxidase A (MAOA) maps to Xp11.23. The longer repeats (3.5R, 4R, and 5R) of a functional polymorphism in the promoter region of the MAOA gene consists of 30-bp upstream repeats (MAOA-uVNTR). The long alleles have been shown to affect the transcription of the gene three to four times more efficiently than the shorter 3R allele [21, 22]. Studies in both humans and animal models have supported the involvement of MAOA in the etiology of externalizing behaviors, especially in males, including impulsivity and aggression [23–26], and ADHD . In our research group, Zhang et al., found a significant preferential transmission of the 3R allele of MAOA-uVNTR to ADHD among boys (P = 0.01), and also the inattentive subtype of ADHD in boys (P = 0.02). Zhang et al. found no association between MAOA-uVNTR and ADHD among boys comorbid with ODD.
Since our previous association studies between ADHD clinical phenotypes and these two functional polymorphisms consistently showed the low transcriptional activity alleles were preferentially transmitted to the inattentive subtype of ADHD in boys, and because these polymorphisms are all involved in the probable etiology of externalizing behaviors, the goal of the present study is to test the hypothesis that COMT Val158Met and MAOA-uVNTR jointly contribute to the phenotype of ADHD-IA with comorbid oppositional defiant disorder (ODD) in a clinical sample of Chinese male subjects.