ORIGINAL ARTICLES Association Between Alpha-2a-adrenergic Receptor Gene and ADHD Inattentive Type Marcelo Schmitz, Daniel Denardin, Tatiana Laufer Silva, Thiago Pianca, Tatiana Roman, Mara Helena Hutz, Stephen V. Faraone, and Luis Augusto Rohde Background: Previous investigations have demonstrated that an MspI polymorphism at the adrenergic 2A receptor gene (ADRA2A) is associated with severity of attention-deficit/hyperactivity disorder (ADHD) inattentive symptoms in clinical samples composed mainly of subjects with ADHD, combined type. This study aimed to investigate the association between this ADRA2A polymorphism and attention-deficit/hyperactivity disorder–inattentive type (ADHD-I) in a nonreferred sample. Methods: In a case– control study, we assessed a sample of 100 children and adolescents with ADHD-I and 100 non-ADHD controls. Cases and controls were matched by gender and age and were screened by using teacher reports in a revised version of the Swanson, Nolan, and Pelham rating scale at 12 schools. Psychiatric diagnoses were derived through structured diagnostic interviews. Results: Homozygous subjects for the G allele at the ADRA2A had significantly higher odds ratio (OR) for ADHD-I than did those with other genotypes (CC  CG genotypes), even after adjusting for potential confounders (p  .02; OR  3.78; 95% confidence interval  1.23–11.62). In family-based analyses, no significant associations were detected. Conclusions: Our results suggest that the ADRA2A may be associated with ADHD-I, replicating previous findings from clinical samples that have suggested the importance of this gene for the dimension of inattention. In addition, these results support the role of the noradrenergic system in ADHD. Key Words: ADRA2A gene, adrenergic receptors, attention-deficit/ hyperactivity disorder–inattentive type, candidate genes, children, molecular genetics A ttention-deficit/hyperactivity disorder (ADHD) is one of the most common mental disorders affecting children and adolescents, with an estimated prevalence ranging from 3% to 10% (American Psychiatric Association 1994; Faraone et al 2003; Rohde et al 1999). The causes of ADHD remain unclear, but investigations involving ADHD families, twin siblings, and adopted children have described ADHD as highly heritable, suggesting a strong genetic influence (Faraone et al 2005). Although dopaminergic genes are yet the most studied in ADHD (Biederman and Faraone 2005), genes related to the noradrenergic system also have been the focus of investigation in recent studies (Bobb et al 2005; Roman et al 2002, 2006). Among several noradrenergic genes, those encoding adrenergic recep- tors are good candidate genes for ADHD. Animal-based studies and clinical investigations suggest that noradrenergic projections to the prefrontal cortex improve cortical functions related to ADHD, such as working memory, basically through postsynaptic 2 receptors (Arnsten and Li 2005; Arnsten et al 1996; Biederman and Spencer 1999; Franowicz and Arnsten 1998; Jakala et al 1999). Among the several types of 2 receptors in the brain, 2A is very promising because of its presence in many cerebral regions. Moreover, it is the most prevalent noradrenergic recep- tor in the prefrontal cortex (Arnsten et al 1996), and it is the site of action of guanfacine and clonidine, drugs that are used to treat ADHD (Biederman and Faraone 2005). The 2A adrenoreceptor gene (ADRA2A) is located in chro- mosome 10q24 –26. A 1291 C¡G single-nucleotide polymor- phism (SNP), creating an MspI site in the promoter region of the gene, was identified by Lario et al (1997). Seven studies evalu- ated the association between this ADRA2A polymorphism and ADHD (Comings et al 1999; Park et al 2004; Roman et al 2003, 2006; Stevenson et al 2005; Wang et al 2006; Xu et al 2001). In our first study, we found an association between the GG genotype at ADRA2A gene and inattentive scores in a sample of 92 subjects with ADHD (Roman et al 2003). In a subsequent independent sample of children with the disorder, the association between inattentive symptoms and the GG genotype again was detected (Roman et al 2006). Similar findings also were obtained by Park et al (2004). Those investigators investigated a possible role of ADRA2A gene in ADHD by assessing three different SNPs, including the 1291 C¡G SNP. A significant effect of this polymorphism was detected through quantitative TDT (QTDT) in both inattentive and hyperactive–impulsive symptom dimen- sions, particularly through the G allele, replicating our findings. Moreover, haplotype analyses showed significant effects of this polymorphism by either TDT or QTDT. In both cases, the G allele of 1291 C¡G SNP appeared to contribute to an increased risk, especially when inattentive symptoms were considered. However, Xu et al (2001) did not find a role for this polymor- phism in a family association study with ADHD probands. None of these studies investigated specifically the association of the ADRA2A gene and ADHD–inattentive type, and all used clinically referred samples. Previous studies on other psychiatric diseases consistently have suggested that clinical heterogeneity may obscure a positive finding in molecular genetic studies because it frequently is associated with etiological heterogeneity (State et al 2000). Therefore, the reduction of ADHD’s clinical heterogeneity through the selection of specific ADHD types appears to be a rationale strategy, because groups with specific biological and environmental components may be identified (Faraone et al 1998; Woo and Rey 2005) In addition, several studies have indicated differences in social, academic, and behavioral func- From the ADHD Outpatient Clinic (MS, DD, TLS, TP, LAR) Child and Adoles- cent Psychiatric Division, Hospital de Clínicas de Porto Alegre; the De- partment of Genetics (MHH), Federal University of Rio Grande do Sul, Porto Alegre, Brazil; the Department of Morphological Sciences (TR), Federal School of Medical Sciences of Porto Alegre, Porto Alegre, Brazil; and the Department of Psychiatry (SVF), Upstate Medical University, Syracuse, New York. Address reprint requests to Luis Augusto Rohde, Sc.D., Serviço de Psiquiatria da Infância e Adolescência, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Rua Ramiro Barcelos, 2350, Porto Alegre, Rio Grande do Sul, Brazil 90035-003; E-mail: lrohde@terra.com.br. Received October 31, 2005; accepted February 23, 2006. BIOL PSYCHIATRY 2006;60:1028 –1033 0006-3223/06/$32.00 doi:10.1016/j.biopsych.2006.02.035 © 2006 Society of Biological Psychiatry