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Abstract: Attention-deficit hyperactivity disorder (ADHD) is a clinically complex and multifactorial psychiatric disorder of inattention, hyperactivity and impulsivity. Family, twin and adoption studies suggest a genetic influence in the etiology of ADHD. Two variable number of tandem repeats (VNTR) polymorphic systems have been frequently associated with this disorder: the 7 repeat (R) allele in exon 3 of the dopamine receptor D4 (DRD4) and the 10R allele located in the 3′ untranslated region (UTR) of the dopamine transporter (DAT1). We conducted a case–control association study between ADHD and these polymorphisms in a group of adolescent inhabitants of the metropolitan area of Mexico City. In addition, we evaluated the interaction between these genes, the disorder and its associated psychiatric comorbidities. No positive association between ADHD and the 7R allele of DRD4 or the 10R allele of DAT1 was observed; however, compared to controls, patients with internalized comorbidities had a lesser frequency of genotypes with the 7R allele of DRD4 and the 10/10 genotype of DAT1. A logistic regression analysis showed that the simultaneous absence of the 10/10 DAT1 and 7/7 DRD4 genotypes predicts membership to the group of ADHD patients with internalized comorbidities (e.g. anxiety, depression). Our results highlight the importance of cross-ethnic research and the possibility of a distinct genetic basis that underlies the type of comorbidities associated with ADHD. This result should be considered in terms of the study design, and further replication is necessary in an independent sample. [Copyright &y& Elsevier]