Based on pre-DNA racial/color methodology, clinical and pharmacological trials have traditionally considered the different geographical regions of Brazil as being very heterogeneous. We wished to ascertain how such diversity of regional color categories correlated with ancestry. Using a panel of 40 validated ancestry-informative insertion-deletion DNA polymorphisms we estimated individually the European, African and Amerindian ancestry components of 934 self-categorized White, Brown or Black Brazilians from the four most populous regions of the Country. We unraveled great ancestral diversity between and within the different regions. Especially, color categories in the northern part of Brazil diverged significantly in their ancestry proportions from their counterparts in the southern part of the Country, indicating that diverse regional semantics were being used in the self-classification as White, Brown or Black. To circumvent these regional subjective differences in color perception, we estimated the general ancestry proportions of each of the four regions in a form independent of color considerations. For that, we multiplied the proportions of a given ancestry in a given color category by the official census information about the proportion of that color category in the specific region, to arrive at a “total ancestry” estimate. Once such a calculation was performed, there emerged a much higher level of uniformity than previously expected. In all regions studied, the European ancestry was predominant, with proportions ranging from 60.6% in the Northeast to 77.7% in the South. We propose that the immigration of six million Europeans to Brazil in the 19th and 20th centuries - a phenomenon described and intended as the “whitening of Brazil” - is in large part responsible for dissipating previous ancestry dissimilarities that reflected region-specific population histories. These findings, of both clinical and sociological importance for Brazil, should also be relevant to other countries with ancestrally admixed populations.

We documented the effect of the G allele at the ADRA2A -1291 C>G polymorphism on the improvement of inattentive symptoms with methylphenidate treatment in children and adolescents with ADHD. Our findings provide clinical evidence for the involvement of the noradrenergic system in the modulation of methylphenidate action.

Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric condition that affects approximately 5.3% of children worldwide. This disorder is defined by a combination of symptoms of inattention and hyperactivity/impulsivity. Diagnosis is based on impairment in these two domains determining several problems in personal and academic life. Although it is known that genetic and environmental factors are important in ADHD etiology, how these factors influence the brain and consequently behavior is still under debate. There seems to be a consensus in the literature that a fronto-subcortical dysfunction is responsible, at least in part, for the ADHD spectrum. Considering that these brain regions are rich in dopamine (DA), the DA hypothesis has an important role to understand ADHD pathophysiology. The main goal of the present review is to show evidence from different areas that support the idea that dysregulation in the DA system underlies ADHD. We discuss here evidences from animal models, pharmacology, brain imaging and genetics studies.

Catecholaminergic imbalance has increasingly been implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). The enzyme dopamine-beta-hydroxylase (D beta H)-critical to catecholaminergic regulation-is under strong genetic control, with the -1021 C/T polymorphism accounting for up to 50% of the enzymatic activity. This work aimed to investigate association between this functional polymorphism and the performance of children and adolescents with ADHD in neuropsychological measures of executive function (EF). Sixty-four drug-naive patients with ADHD undertook a Continuous Performance Test and the Wisconsin Card Sorting Test. By means of a factorial analysis, a composite measure of EF was extracted. Performance according to genotypic group was analyzed, including age as a confounder. In addition, a family-based association test was conducted as a confirmatory analysis. Principal components analysis of neuropsychological measures loaded two factors that explained 83.8% of total variance. Cognitive performance, as measured by the composite score, showed significant difference between genotypic groups after adjustment for age (P = 0.002). The CC homozygosity was associated with a diminished global EF performance, a result that was corroborated by the intra-familial analysis. The present study demonstrated an association between the neuropsychological performance of children with ADHD and a functional polymorphism in the promoter region of the DBH gene. The refinement of the ADHD phenotype by means of composite measures of EF can contribute to uncover the molecular underpinnings of ADHD.

Few studies on pharmacogenetics of Attention-Deficit/Hyperactivity Disorder (ADHD) have been conducted. Most of them evaluated dopaminergic genes resulting in positive and negative findings. We assessed effects of polymorphisms in candidate dopaminergic (DRD4, DAT1) and serotonergic genes (HTR1B, HTR2A, and 5-HTT) on the response to treatment in 111 patients for whom methylphenidate (MPH) was prescribed. Outcome measures (Swanson, Nolan, and Pelham scale-version IV, Children Global Assessment Scale, Barkley's Stimulants Side Effects Rating Scale) were assessed at baseline and 1 month after the intervention. No significant association was detected between polymorphisms assessed and both response and side effects to MPH. Prospective multi-site controlled studies with larger sample sizes are needed in order to disentangle the role of candidate genes in response to ADHD treatment.