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The dopamine transporter (SLC6A3/DAT1) plays a key role in the regulation of dopaminergic neurotransmission and is the major site of action for methylphenidate, a first-line medication for attention deficit hyperactivity disorder (ADHD). Most genetic association studies with ADHD have investigated a 40-bp variable number of tandem repeats (VNTR) polymorphism in the 3'-untranslated region (UTR) of the DAT1, but these investigations have reported heterogeneous findings. The few studies focused on the 5' region have reported promising results. Despite rs2652511 not being included, nor having any proxy SNP available in GWAS, the few candidate gene studies that analyzed it suggested an association with ADHD and schizophrenia. Here, we analyzed the -839 C/T (rs2652511) promoter variant and the 3'-UTR and intron 8 (Int8) VNTR polymorphisms in 522 adults with ADHD and 628 blood donor controls. The diagnostic procedures followed the DSM-IV criteria. A significant association was detected (P = 0.002) between the rs2652511 C-allele with ADHD. In addition, the 6-repeat allele of Int8 VNTR was associated with higher inattention scores (P = 0.034). The haplotype analysis including DAT1 3'-UTR and Int8 VNTR polymorphisms did not reveal associations with ADHD susceptibility or severity dimensions. These findings extend to adult samples previous findings from children samples on the role of the rs2652511 polymorphism in the promoter region of DAT1 as a risk factor for ADHD susceptibility.

Several studies have tested for the association between polymorphisms in the ADRA2A gene and childhood ADHD. A meta-analysis of these results, however, has pointed towards a significant heterogeneity, raising the need for explanatory studies. As the effect of other relevant clinical characteristics could be a possible source, we studied three polymorphisms in the ADRA2A gene (-1291 C>G-MspI or rs1800544; -262 G>A-HhaI or rs1800544; 1780 C>T-DraI or rs553668) in 403 adult patients with ADHD assessed in relation to comorbidity and personality characteristics, as well as in 232 controls. The diagnosis followed DSM-IV criteria, and personality dimensions were evaluated with the Temperament and Character Inventory (TCI). There were no significant differences in allele and genotype frequencies between cases and controls. Patients carrying the G allele of rs1800544 presented lower scores in harm avoidance, and carriers of the T allele of rs553668 had more novelty seeking and less harm avoidance and persistence. Additionally, the haplotype carrying the G-G-T alleles (rs1800544-rs1800545-rs553668) was associated with lower scores in harm avoidance and persistence, and higher scores in novelty seeking compared to other haplotypes. These findings suggest that the conflicting findings obtained in association studies between ADRA2A polymorphisms and ADHD might be related to temperament profiles, and support additional studies addressing these effects in larger samples., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Several lines of evidence suggest a relevant role for the dopamine transporter (DAT1) gene not only as a susceptibility factor for attention-deficit hyperactivity disorder (ADHD), but also as a predictor of individual methylphenidate (MPH) response. Pharmacogenetic studies of MPH response in ADHD have mainly focused on the 40-bp variable number of tandem repeats (VNTR) in the 3' untranslated region (3'-UTR) of DAT1. Most studies were performed in samples of children and conflicting findings were obtained. Only two studies have assessed 3'-VNTR in samples of adults-one with positive and the other with negative findings. In the present study, we investigate three potentially relevant polymorphisms in DAT1 gene (-839 C > T; Int8 VNTR and 3'-VNTR), and their possible role in therapeutic response to MPH treatment in a sample of 171 Brazilian adults with ADHD. The diagnostic procedures followed the DSM-IV criteria and the outcome measures were the scales Swanson, Nolan, and Pelham Rating scale version IV and the Clinical Global Impression-Severity Scale, applied at the beginning and after the 30th day of treatment. Drug response was assessed by both categorical and dimensional approaches. There was no effect of any DAT1 polymorphisms or haplotypes on MPH response. This is the second report demonstrating absence of differences in MPH response according to DAT1 genotypes in adults with ADHD. Although DAT protein is crucial for the effect of MPH, genetic variations in DAT1 gene probably do not have a significant clinical role in this sample of adults with ADHD.

The present study investigates possible associations between the 5-HTT control region polymorphism (5-HTTLPR) with adult ADHD, including subtypes, severity, temperament profile and comorbidities. The polymorphic site was genotyped in 312 adult patients with ADHD and 236 controls, all of them Brazilians of European descent. The interviews followed the DSM-IV criteria, using the K-SADS-E for ADHD and oppositional defiant disorder, SCID-I and MINI for comorbidities and the TCI for temperament dimensions. The 5-HTTLPR polymorphism was not associated with ADHD. Carriers of the S allele presented slightly higher inattention and novelty seeking scores, and a higher frequency of drug dependence. These differences do not persist after correction for multiple comparisons. These results suggest that the 5-HTTLPR polymorphism does not have a direct role in the predisposition to adult ADHD. There is suggestive evidence for a small effect in some behavioral phenotypes related to ADHD.

The T allele of the C825T polymorphism in the G-protein beta(3) subunit gene (GNB3) is related to the increase of signal transduction by the G-protein. G-proteins are intermediary paths in signal transduction from receptors involved in mood regulation and substance dependence. We studied the C825T polymorphism in individuals with (i) alcohol and nicotine dependence (n = 109), (ii) nicotine dependence only (n = 117) and (iii) non-dependent controls (n = 108). We also tested for possible associations with psychiatric comorbidities among alcohol-dependent individuals. No differences were detected for allele and genotype frequencies in individuals with or without dependencies. Alcohol-dependent individuals with the heterozygous genotype presented more frequently major depressive disorder (chi(2) = 12.34; p = 0.002). These findings, taken together with other studies suggesting an influence of the C825T polymorphism in major depressive disorder, support the hypothesis of the involvement of G-proteins in mood regulation.

The aim of the present study is to test for possible associations between the C-1291G polymorphism in the alpha2A-adrenergic receptor gene (ADRA2A) with tobacco smoking and alcohol dependence. The genotype and allele frequencies were compared in three groups of European-derived Brazilian males: individuals with co-occurrence of tobacco smoking and alcohol dependence (N = 110), with tobacco smoking (N = 121) and controls (N = 114). The frequency of the G allele was higher in the group with both conditions, intermediate among subjects with smoking, and lower among controls (chi(2) = 8.00; p = 0.02). The chi(2) partitioning did not reveal significant differences between the sample with the two conditions and the sample of smokers (chi(2) = 0.82; p = 0.36). Combining both groups, the difference to the non-smoking controls is higher than the one observed in the three-groups analysis (chi(2) = 7.18; p = 0.007). The results suggest a role for the ADRA2A C-1291G polymorphism, notably the G allele, in the predisposition to tobacco smoking. The influence of the ADRA2A gene in nicotine and other substance dependencies should be more extensively assessed in future studies.

Objective: The role of the human serotonin transporter protein (5-HTT) gene in psychiatric disorders suggests that its variation may influence the comorbidity pattern and the heterogeneity of alcoholism. The aim of the present study is to verify possible associations between the 5-HTTLPR control region polymorphism with alcoholism and comorbid disorders., Methods: The polymorphic site was genotyped in 114 patients with alcohol dependence and 218 controls, all of them Brazilians of European descent. A comprehensive diagnostic interview identified the comorbid disorders., Results: Study participants with alcohol dependence and controls did not differ in the genotype and allele frequencies (genotypes: chi(2) = 2.52, P = 0.28; alleles: chi(2) = 0.37; P = 0.54). Patients with comorbid major depressive disorder (chi(2) = 6.14, P = 0.01), drug abuse (chi(2) = 6.82, P = 0.01) and nicotine dependence (chi(2) = 4.10, P = 0.04), however, presented a higher frequency of the S allele than patients without these comorbidities. Patients with comorbid depression and drug abuse also presented a higher frequency of the S allele than controls., Conclusions: The present results are consistent with the importance of the 5-HTT gene in psychiatry. They suggest a role of the 5-HTTLPR polymorphism in a group of comorbid disorders among alcohol-dependent individuals, supporting a genetic influence in alcoholism heterogeneity.

The enzyme monoamine oxidase A (MAO A) plays an important role in the metabolism of neurotransmitters. The MAOA gene presents several polymorphisms, including a 30-bp VNTR in the promoter region (MAOA-uVNTR). Alleles with 3.5 and 4 repeats are 2-10 times more efficient than the 3-repeat allele. Several studies have shown an association between the 3-repeat allele and a cluster of externalizing behaviors including alcoholism, antisocial personality, and impulsivity. The objective of the present study is to replicate in a different culture the associations between the MAOA-uVNTR with alcoholism and other phenotypes. The sample comprises 125 Brazilian alcoholics of European descent and 235 controls. The results suggest that the 3-repeat allele is associated to: (1) alcohol dependence (P < 0.05); (2) an earlier onset of alcoholism (P < 0.01); (3) comorbid drug abuse among alcoholics (P < 0.05); and (4) a higher number of antisocial symptoms (P < 0.02). Our results confirmed previous reports showing an association of the low activity 3-repeat allele of MAOA-uVNTR polymorphism with substance dependence and impulsive/antisocial behaviors. These findings in a different culture further support the influence of the MAOA-uVNTR in psychiatric disorders., (Copyright 2006 Wiley-Liss, Inc.)

The DRD2 TaqI A and DBH-1021 C/T polymorphisms were genotyped in smoking alcoholics (N = 100), non-alcoholic smokers (N = 120) and nonsmoking controls (N = 112). Alcoholic and non-alcoholic smokers presented a higher frequency of the DRD2 TaqI A1 allele (P = 0.04) than non-smoking controls. Individuals who had at least one DBH-1021 T allele smoked fewer cigarettes per day than CC homozygotes (P = 0.03). These results are coherent with the expected effects of these polymorphisms on dopaminergic function.