Neuroscience Letters 451 (2009) 257–260 Contents lists available at ScienceDirect Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet Genetic interaction analysis for DRD4 and DAT1 genes in a group of Mexican ADHD patients Martínez-Levy Gabriela a , Díaz-Galvis John a , Briones-Velasco Magdalena a , Gómez-Sánchez Ariadna a , De la Pe ˜ na-Olvera Francisco b , Sosa-Mora Liz b , Palacios-Cruz Lino b , Ricardo-Garcell Josefina b , Reyes-Zamorano Ernesto b , Cruz-Fuentes Carlos a,∗ a Laboratorio de Genética Psiquiátrica, Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría “Ramón de la Fuente Mu˜ níz”, Mexico City, Mexico b Clínica de adolescentes, Dirección de Servicios clínicos, Instituto Nacional de Psiquiatría “Ramón de la fuente Mu˜ níz” México D. F., Mexico article info Article history: Received 8 September 2008 Received in revised form 28 November 2008 Accepted 1 January 2009 Keywords: Attention deficit hyperactivity disorder Dopamine D4 receptor gene Dopamine transporter gene Genetic interaction Internalized and externalized comorbidities Mexican abstract Attention-deficit hyperactivity disorder (ADHD) is a clinically complex and multifactorial psychiatric dis- order 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 trans- porter (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. © 2009 Elsevier Ireland Ltd. All rights reserved. Attention-deficit hyperactivity disorder (ADHD) is a common childhood-onset psychiatric syndrome of hyperactivity, impulsivity and impaired sustained attention. This disorder has a prevalence of 4–12% in the school-aged population with 50–80% of patients experiencing symptoms that persist through adolescence and into adulthood [34]. Social dysfunction and skill deficits associated with ADHD may have a significant impact on the labor and academic life of affected individuals [1,8]. It has been estimated that 20–55% of ADHD patients express other externalized psychiatric disorders (e.g. conduct disorder, oppositional defiant disorder), whereas approximately 10–50% express internalized (e.g. anxiety, depression) comorbidites, lead- ing to the conceptualization of ADHD as a clinically heterogeneous entity [2,17,34]. Furthermore, it has been reported that these char- ∗ Corresponding autor at: Psychiatric Genetic Department, Clinical Research Branch, Instituto Nacional de Psiquiatría “Ramón de la Fuente Mu˜ níz”, Calzada México-Xochimilco 101, San Lorenzo Huipulco, Tlalpan CP 14370, México, D.F., Mex- ico. Tel.: +55 56552811x210; fax: +55 55133722. E-mail address: cruz@imp.edu.mx (C.-F. Carlos). acteristics are aggregated in families [7], leading to some authors to propose that the study of these comorbidities may help in the classification of different ADHD subtypes [7,13,22]. Attention-deficit hyperactivity disorder is regarded as a her- itable, complex and multifactorial disorder that involves the interaction of biological and environmental factors [1,36]. Phar- macological studies, animal models and brain images have all demonstrated that catecholamine neural pathways are relevant for understanding the neurobiological basis of this disorder. Specifi- cally, it has been proposed that alterations in the cerebral dopamine system partially explain the cardinal symptoms and effectiveness of pharmacological treatments [5,15,39]. Thus, genes encoding dopamine-related proteins have been evaluated in relation with ADHD [12,15,24]. In particular, two polymorphic systems have been the focus of many published studies: a variable number of tandem repeats (VNTR) in exon III of the dopamine D4 receptor gene (DRD4) and the VNTR located on the 3 ′ untranslated region (3 ′ -UTR) of the dopamine transporter gene (SCL6A3 or DAT1) [15,16,36]. Several metanalysis have concluded that the 7 repeat (R) allele of DRD4 yield a small but statistically significant effect towards the risk of 0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2009.01.004