-
[show abstract]
[hide abstract]
ABSTRACT: Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric condition of children worldwide. This disorder is defined by a combination of symptoms of inattention and hyperactivity/impulsivity. Diagnosis is based on a sufficient number of symptoms causing impairment in these two domains determining several problems in personal and academic life. Although genetic and environmental factors are important in ADHD etiology, how these factors influence the brain and consequently behavior is still under debate. It seems to be consensus that a frontosubcortical dysfunction is responsible, at least in part, for the ADHD phenotype spectrum. The main results from association and pharmacogenetic studies performed in Brazil are discussed. The investigations performed so far on ADHD genetics in Brazil and elsewhere are far from conclusive. New plausible biological hypotheses linked to neurotransmission and neurodevelopment, as well as new analytic approaches are needed to fully disclose the genetic component of the disorder.
Genetics and Molecular Biology 12/2012; 35(4 (suppl)):932-8. · 0.63 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Attention-deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders in children with a worldwide prevalence of 5.3%. Recently, a Korean group assessed the G-protein-coupled receptor kinase-interacting protein 1 (GIT1) gene that had previously been associated with ADHD. In their work, 27 single nucleotide polymorphisms SNPs in the GIT1 gene were tested; however, only the rs550818 SNP was associated with ADHD susceptibility. Moreover, the presence of the risk-associated allele determined reduced GIT1 expression, and Git1-deficient mice exhibit ADHD-like phenotypes. The aim of this study was to determine if this association also occurs in a sample of Brazilian children with ADHD. No effect of GIT1 genotypes on ADHD susceptibility was observed in the case-control analysis. The odds ratios (ORs) were 0.75 (P = 0.184) for the CT genotype and 1.09 (P = 0.862) for the TT genotype. In addition, the adjusted OR of the CT+TT genotypes vs. the CC genotype was also estimated (P = 0.245). There were no dimensional associations between the GIT1 genotypes and both hyperactivity and /impulsivity, and only hyperactivity Swanson, Nolan and Pelham Scale-Version IV (SNAP-IV) scores (P = 0.609 and P = 0.247, respectively). The transmission/disequilibrium test indicated that there was no over-transmission of rs550818 alleles from parents to ADHD children (z = 0.305; P = 0.761). We conclude that rs550818 is not associated with ADHD in this Brazilian sample. More studies are required before concluding that this polymorphism plays a role in ADHD susceptibility.
Genes Brain and Behavior 08/2012; 11(7):864-8. · 3.48 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: COMT Val(158)Met polymorphism has been associated with both symptoms of attention-deficit/hyperactivity disorder (ADHD) and disruptive behavior disorders (DBD): that is, oppositional defiant disorder (ODD) and conduct disorder (CD) often comorbid with ADHD. The aim of this study was to test the association between COMT Val(158)Met polymorphism and the presence of DBD in children with ADHD (n = 516). Homozygous Val/Val children showed a higher prevalence of ADHD comorbid with DBD (χ(2) = 5.762; p = 0.016; OR = 1.58; CI(95%) = 1.07-2.35). Our findings replicate previous results and suggest a role for COMT in the etiology of DBD in children and adolescents with ADHD.
Acta Neurovegetativa 01/2012; 119(6):729-33. · 2.73 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) are highly comorbid and may share a genetic vulnerability. Methylphenidate (MPH), a dopamine transporter (DAT) blocker, is an effective drug for most ADHD patients. Although dopamine D4 receptor (DRD4) and dopamine transporter (DAT1) genes have a role in both disorders, little is known about how these genes influence brain response to MPH in individuals with ADHD/SUDs. The goal of this study was to evaluate whether ADHD risk alleles at DRD4 and DAT1 genes could predict the change in striatal DAT occupancy after treatment with MPH in adolescents with ADHD/SUDs.
Seventeen adolescents with ADHD/SUDs underwent a SPECT scan with [Tc(99m) ]TRODAT-1 at baseline and after three weeks on MPH. Caudate and putamen DAT binding potential was calculated. Comparisons on DAT changes were made according to the subjects' genotype.
The combination of both DRD4 7-repeat allele (7R) and homozygosity for the DAT1 10-repeat allele (10/10) was significantly associated with a reduced DAT change after MPH treatment in right and left caudate and putamen, even adjusting the results for potential confounders (P ≤ 0.02; R² from 0.50 to 0.56).
In patients with ADHD/SUDs, combined DRD4 7R and DAT1 10/10 could index MPH reduced DAT occupancy. This might be important for clinical trials, in terms of better understanding individual variability in treatment response.
Synapse 02/2011; 65(2):154-9. · 2.94 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: there have been few studies evaluating the frequency of oculo-auriculo-vertebral spectrum (OAVS) in patients with congenital heart defects (CHDs).
to verify the frequency of OAVS in a sample of patients with major heart malformations.
we evaluated a prospective cohort of patients with CHD admitted in a pediatric cardiac intensive care unit (ICU) in Brazil. The diagnosis of OAVS was made based on the clinical data, considering standard criteria. The patients that met these criteria were submitted to high resolution GTG-Banding karyotype and fluorescence in situ hybridization for 22q11.2 microdeletion. Fisher's exact test (P < 0.05) was used for the statistical analysis.
During the period of evaluation, 330 patients were hospitalized for the first time in the ICU, but thirty of them did not participate in the study. Of the 300 patients that constituted the final sample, OAVS was verified in 3 cases (1%). All presented normal cytogenetic studies.
OAVS seems to be a frequent condition among patients with CHDs. However, we cannot exclude the possibility that the frequency of OAVS found in our study might have been underestimated due to the low rate of prenatal detection of CHDs and the limited access of patients to appropriate health care in our region. Future prospective studies with well defined clinical criteria and subjects with mild and major defects will be important to assess the role of OAVS in the general population of subjects with heart malformations.
Arquivos brasileiros de cardiologia 10/2010; 95(4):436-9. · 1.32 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) has a moderate to high genetic component, probably due to many genes with small effects. Several susceptibility genes have been suggested on the basis of hypotheses that catecholaminergic pathways in the brain are responsible for ADHD. However, many negative association findings have been reported, indicating a limited success for investigations using this approach. The results from genome-wide association studies have suggested that genes related to general brain functions rather than specific aspects of the disorder may contribute to its development. Plausible biological hypotheses linked to neurotransmission and neurodevelopment in general and common to different psychiatric conditions need to be considered when defining candidate genes for ADHD association studies.
Genome Medicine 11/2009; 1(11):107.
-
Arquivos brasileiros de cardiologia 10/2009; 93(4):e67-9, e55-7. · 1.32 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Several evidences suggested that the serotonin 5-HT1B receptor gene (HRT1B) might be involved in the susceptibility to attention deficit/hyperactivity disorder (ADHD). Prior studies reported excess transmissions of the HRT1B gene 861G allele to affected ADHD children and of a haplotype block containing this variant and two functional promoter SNPs to probands with ADHD-inattentive subtype. However, some investigations did not replicate these findings. Therefore, we tested for biased transmissions of haplotypes derived from the 861G > C, -161A > T, and -261T > G SNPs from parents to 343 families with ADHD children. We also sought to replicate findings from the literature that the association between HTR1B is preferentially with ADHD-Inattentive subtype. Using a transmission disequilibrium test we found evidence for an excess transmission of haplotype. -261G/-161T/861G (P = 0.014) for affected children in the total sample. When the analysis was repeated with 143 families with ADHD-Inattentive subtype no significant associations were observed. Our results provide additional evidence that HRT1B gene may be an important risk factor for the development of ADHD, but this effect seems not to be attributable to inattentive cases.
Acta Neurovegetativa 09/2009; 116(12):1675-80. · 2.73 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The monoamine oxidase A (MAOA) gene has been extensively related to aggressive, impulsive and violent behaviours. Previous studies have documented the improvement of oppositional symptoms in attention deficit hyperactivity disorder (ADHD) patients with methylphenidate (MPH). However, the effect of the MAOA gene in response to MPH has not been investigated. A sample of 85 boys from an ADHD outpatient service was genotyped for the MAOA-uVNTR polymorphism. The outcome measure was the parent-rated oppositional subscale of the Swanson, Nolan and Pelham Scale - version IV. The scale was applied by child psychiatrists blinded to genotype at baseline and in the first and third months of treatment. A significant interaction between the presence of MAOA high-activity genotype and treatment with MPH over time on oppositional scores was detected during the 3 months' treatment (n=85, F2,136=4.83, p=0.009). These results suggest an effect of the MAOA-uVNTR high-activity genotype on the improvement of oppositional symptoms with MPH treatment.
The International Journal of Neuropsychopharmacology 04/2009; 12(5):709-14. · 4.58 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The dopamine transporter (DAT) is the major site of methylphenidate action, which is one of the main drugs used to treat attention-deficit/hyperactivity disorder (ADHD). Most association studies with ADHD focused in a VNTR at the 3'-untranslated region of the gene (3'UTR) presenting conflicting results. However, the most common explanation to inconsistent results is variable linkage disequilibrium with an adjacent functional variant, just a few number of DAT1 studies have reported LD structure across the gene. In this study, we screened 16 polymorphisms across the DAT1 gene to understand LD structure in a Brazilian sample of families with ADHD probands and to verify if there were evidence for a biased transmission of alleles and haplotypes from parents to their 243 children with ADHD. In the DSM-IV combined subtype, we observed a preferential transmission of the haplotype A/C/C/C/A derived from five SNPs (rs2550948, rs11564750, rs261759, rs2652511, rs2975223) in 5' region (P corrected = 0.018) and no association with any allele/haplotype at the 3' region of the gene, including the 3' VNTR and the VNTR of intron 8. These results suggest a role for the promoter region in ADHD susceptibility and that allele heterogeneity should be highly considered in DAT1 gene association studies highlighting the importance of this gene in the genetics of the disorder.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 10/2008; 147B(8):1568-75. · 3.70 Impact Factor
-
Rafael F M Rosa,
Carlo B Pilla,
Vera L B Pereira,
José A M Flores,
Eliete Golendziner,
Dayane B Koshiyama,
Michele T Hertz,
Cláudia P Ricachinevsky, Tatiana Roman,
Marileila Varella-Garcia,
Giorgio A Paskulin
[show abstract]
[hide abstract]
ABSTRACT: The 22q11.2 deletion syndrome (22q11DS) is one of the most recognizable causes of congenital heart defects (CHDs), but the frequency varies in non-selected populations. The purpose of this study was to determine the incidence and clinical features of patients with CHD and 22q11DS admitted to a pediatric cardiology intensive care unit in Brazil. In a prospective study, we evaluated a consecutive series of 207 patients with a CHD following a clinical protocol and cytogenetic analysis by high resolution karyotype and fluorescent in situ hybridization (FISH). 22q11DS was identified in four patients (2%), a frequency similar to studies that evaluated subjects with major CHDs in other countries. Despite this similarity, we believe that the low rate of prenatal identification of CHDs and the limited access of these patients to appropriate diagnosis and care, which occur in our region, could have had an influence on this frequency. It is possible that 22q11DS patients with a severe CHD could have died before having a chance to access a tertiary hospital, leading to an underestimate of its frequency.
American Journal of Medical Genetics Part A 08/2008; 146A(13):1655-61. · 2.39 Impact Factor
-
Rafael F.M. Rosa,
Carlo B. Pilla,
Vera L.B. Pereira,
José A.M. Flores,
Eliete Golendziner,
Dayane B. Koshiyama,
Michele T. Hertz,
Cláudia P. Ricachinevsky, Tatiana Roman,
Marileila Varella-Garcia,
Giorgio A. Paskulin
[show abstract]
[hide abstract]
ABSTRACT: The 22q11.2 deletion syndrome (22q11DS) is one of the most recognizable causes of congenital heart defects (CHDs), but the frequency varies in non-selected populations. The purpose of this study was to determine the incidence and clinical features of patients with CHD and 22q11DS admitted to a pediatric cardiology intensive care unit in Brazil. In a prospective study, we evaluated a consecutive series of 207 patients with a CHD following a clinical protocol and cytogenetic analysis by high resolution karyotype and fluorescent in situ hybridization (FISH). 22q11DS was identified in four patients (2%), a frequency similar to studies that evaluated subjects with major CHDs in other countries. Despite this similarity, we believe that the low rate of prenatal identification of CHDs and the limited access of these patients to appropriate diagnosis and care, which occur in our region, could have had an influence on this frequency. It is possible that 22q11DS patients with a severe CHD could have died before having a chance to access a tertiary hospital, leading to an underestimate of its frequency. © 2008 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A 06/2008; 146A(13):1655 - 1661. · 2.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 05/2007; 144B(3):391-4. · 3.70 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The dopamine transporter (DAT) plays a key role in the regulation of dopaminergic neurotransmission and is also the major site of action for methylphenidate which is one of the main drugs used to treat attention deficit hyperactivity disorder (ADHD). Most association studies with ADHD have concentrated on the 3'-untranslated region of the gene (3'-UTR) mainly in a variable number of tandem repeat (VNTR) polymorphism, but these investigations have reported discordant results. In this study, we tested this VNTR polymorphism and an additional promoter polymorphism -839 C>T (Rs: 2652511) using family-based association analyses in a sample of 243 Brazilian ADHD children and adolescents and their parents. No significant linkage disequilibrium between the two polymorphisms was detected in this sample (D' = 0.56; P = 0.22). No evidence of association with the VNTR polymorphism was found. A significant association (P = 0.03) for biased transmission of the C allele at the -839 C>T polymorphism to ADHD children in the total sample was observed, which was strengthened when the analyses were restricted to the ADHD combined type (P = 0.004). Our results suggest a role for the promoter region of DAT1 gene in ADHD susceptibility in this Brazilian sample.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 04/2007; 144B(2):215-9. · 3.70 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Attention-deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders of childhood. The role of genetic factors in its etiology is strongly supported by family, adoption, and twin studies. Low serotonin activity has been associated in both animal and human studies with measures of impulsivity, aggression, and disinhibited behaviors, which make genes from the serotonin system reasonable candidates for ADHD susceptibility. In the present study, we investigated a polymorphism in the promoter region of the serotonin transporter (SLC6A4) and two polymorphisms (-1438 A > G and His452Tyr) in the serotonin 5-HTR2A receptor gene using family based association analyses in a sample of 243 Brazilian ADHD children and adolescents and their parents. No linkage disequilibrium between the two HTR2A polymorphisms was detected in this sample (P = 0.76). Considering several evidences from animal models for sexual dimorphism in serotonin genes expression, analyses were performed separately for the whole sample and for male probands. No evidences for biased transmissions of both HTR2A -1438 A > G and SLC6A4 polymorphisms to ADHD youths were observed. Preferential transmission of the HTR2A His452 allele was observed only in families with affected boys (P = 0.04). Our results suggest that findings from ADHD association studies for serotonin genes might be understood in the context of a gender effect, which may help to explain conflicting results in these association studies.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 02/2007; 144B(1):69-73. · 3.70 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Preclinical studies have demonstrated the relevance of adrenergic alpha2A receptor on the attentional process and the mechanism of action of methylphenidate hydrochloride. Several molecular genetic investigations suggest a role for the adrenergic alpha2A receptor gene (ADRA2A) in attention-deficit/hyperactivity disorder (ADHD), especially in the inattentive dimension. However, the effect of ADRA2A in the response to methylphenidate in humans has not been previously investigated, to our knowledge.
To evaluate the association between the ADRA2A -1291 C>G polymorphism and the clinical response to methylphenidate treatment in children and adolescents with ADHD.
A pharmacogenomic study was undertaken between November 1, 2002, and May 1, 2004, using a nonrandom assignment, quasi-experimental design.
An ADHD outpatient program at a university hospital in Brazil. Patients One hundred six patients consecutively diagnosed as having ADHD were genotyped for the ADRA2A -1291 C>G polymorphism and were included in the analyses. Intervention Short-acting methylphenidate administered in increasing dosages until no further clinical improvement was detected or until limited adverse effects occurred.
The primary outcome measure was the parent-rated inattentive subscale of the Swanson, Nolan, and Pelham Scale version IV. Secondary outcome measures included the Barkley Side Effect Rating Scale and the parent-rated hyperactivity-impulsivity subscale of the Swanson, Nolan, and Pelham Scale version IV. Scales were applied by child psychiatrists blinded to genotype at baseline and at 1 and 3 months of treatment.
A significant interaction effect between the presence of the G allele and treatment with methylphenidate over time on inattentive scores was detected during the 3 months of treatment (n = 106; F(2,198) = 4.30; P = .02).
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.
Archives of General Psychiatry 02/2007; 64(2):218-24. · 12.02 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Previous investigations have demonstrated that an MspI polymorphism at the adrenergic alpha2A 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.
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.
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.
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.
Biological Psychiatry 12/2006; 60(10):1028-33. · 8.28 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The adoption of neuropsychological tests as endophenotypic measures can provide an increased sensitivity to specific dimensions of attention-deficit/hyperactivity disorder (ADHD).
The association between a variable number of tandem repeats polymorphism at the dopamine D4 receptor gene (DRD4) and the performance of children and adolescents with ADHD in a continuous performance test (CPT) was evaluated. The sample comprised 90 clinically referred children and adolescents with ADHD. Errors of omission and commission in the CPT were computed and the number of 48-base pairs tandem repeats in the exon III of DRD4 was assessed.
The presence of a 7-repeat allele was associated with more errors of commission and the homozygosity of the 4-repeat allele was related to fewer errors of commission and omission even after adjusting for age.
These findings bring further evidence on the role of DRD4 polymorphisms on the performance in sustained attention tasks among children and adolescents with ADHD diagnosis.
Biological Psychiatry 12/2006; 60(10):1163-5. · 8.28 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent psychiatric disorder. An impressive volume of literature documents both a strong participation of genetics in its etiology and a high rate of response to medication. However, few studies on the pharmacogenomics of ADHD have been conducted to date. This systematic review aims to present a critical discussion of findings from recent investigations. The majority of studies have focused on individual polymorphisms of the dopaminergic genes, with special emphasis on variants of the dopamine transporter gene (DAT1). Almost all studies have assessed the effects of genes in the response to methylphenidate (MPH). Some preliminary results suggest an association between homozygosity for the 10-repeat allele at DAT1 and poor response to MPH. However, other studies have reported contrasting findings. Very few investigations addressed the role of non-dopaminergic genes or gene-gene interactions in ADHD pharmacogenomics. Recent findings suggesting an association between response to MPH and an MspI polymorphism in the promoter region of the alpha2A-adrenoceptor gene (ADRA2A) are discussed. Pharmacogenomic studies of ADHD are in their infancy, and comparability between studies is difficult due to the use of different methodological approaches. As such, multi-site collaborative efforts to obtain larger samples with standardized methodology should be encouraged.
Pharmacogenomics 05/2005; 6(3):225-34. · 3.97 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Neuroimaging studies have suggested the involvement of several brain areas in attention-deficit/hyperactivity disorder (ADHD). Genetic investigations have supported the role of both dopamine D4 receptor gene (DRD4) and dopamine transporter gene (DAT1) in the vulnerability to the disorder. This study evaluates whether the presence of risk alleles at DRD4 and/or DAT1 genes is associated with differences in regional cerebral blood flow (rCBF) in a sample of ADHD boys. The rCBF was compared between ADHD patients with and without risk alleles at DRD4 (7-repeat allele) and/or at DAT1 (homozygosis for the 10-repeat allele) genes by single photon emission computed tomography (SPECT) during continuous performance test. Images were analyzed using statistical parametric mapping (SPM-99). No significant differences in rCBF were found both between ADHD boys with and without the 7-repeat allele at DRD4 locus, as well as between ADHD boys homozygous for the 10-repeat allele and ADHD subjects with other genotypes at the DAT1 locus. However, a significantly higher perfusion in the right middle temporal gyrus was found in the group with risk alleles at both DRD4 and DAT1 loci (n = 6) compared to ADHD boys without risk alleles at both loci (n = 28) (P < 0.05). Our findings suggest that a higher recruitment in middle temporal gyrus, an area associated to working memory and selective attention, should exist to compensate a putative effect of the interaction between these dopaminergic genes.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 01/2005; 132B(1):53-8. · 3.70 Impact Factor
