Effects of NR3C1 and COMT Genes on Attention‐Deficit/Hyperactivity Disorder and Accompanying Aggressiveness: A Cross‐Sectional Study in a Clinical Sample

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition characterized by developmentally inappropriate inattention, hyperactivity-impulsivity, increased distractibility and impairments in executive functioning and behavioural self-regulation. Aggressive behaviours and anger dysregulation are frequently observed across a range of psychiatric conditions, including ADHD and disruptive behaviour disorders, and have been hypothesized to reflect, in part, shared biological and genetic mechanisms. In this study, we investigated whether genetic variation in COMT and NR3C1 is associated with aggression-related phenotypes in youth with ADHD, including physical aggression, verbal aggression and hostility/resentment. METHODS: The case group comprised 69 children and adolescents with ADHD and comorbid aggression, and the control group comprised 111 children and adolescents with ADHD without comorbid aggression. Parents completed a sociodemographic form, the LEVEL 2-Anger Scale (ages 6-17), and the Turgay DSM-IV Disruptive Behaviour Disorders Rating Scale. To evaluate psychiatric comorbidity and cognitive functioning, participants were assessed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version and the Wechsler Intelligence Scale for Children-Revised. Peripheral blood samples were obtained and analysed for COMT and NR3C1 genotype and allele frequencies. RESULTS: Hostility/resentment was significantly associated with COMT genotypes (p = 0.037) and COMT allele distribution (p = 0.015). In addition, the presence of aggression was significantly associated with COMT allele distribution (p = 0.024). However, these statistically significant findings were no longer significant after advanced statistical analysis. In addition, no statistically significant associations were observed between NR3C1 variation and any aggression phenotype or hostility/resentment. CONCLUSION: These findings suggest that COMT-related genetic variation may be associated with aggression-related features in youth with ADHD, whereas no such association was observed for both COMT and NR3C1 in this sample with advanced statistical analysis. Further studies with larger samples and more refined phenotyping are warranted to clarify the genetic architecture underlying aggression in ADHD.