Publications by authors named "Claiton H D Bau"

65 Publications

The role of glucocorticoid receptor gene in the association between attention deficit-hyperactivity disorder and smaller brain structures.

J Neural Transm (Vienna) 2021 Oct 5. Epub 2021 Oct 5.

ADHD Outpatient Program, Adult Division, Hospital de Clínicas de Porto Alegre, Avenida Bento Gonçalves, 9500, Porto Alegre, RS, Brazil.

ADHD is associated with smaller subcortical brain volumes and cortical surface area, with greater effects observed in children than adults. It is also associated with dysregulation of the HPA axis. Considering the effects of the glucocorticoid receptor (NR3C1) in neurophysiology, we hypothesize that the blurred relationships between brain structures and ADHD in adults could be partly explained by NR3C1 gene variation. Structural T1-weighted images were acquired on a 3 T scanner (N = 166). Large-scale genotyping was performed, and it was followed by quality control and pruning procedures, which resulted in 48 independent NR3C1 gene variants analyzed. After a stringent Bonferroni correction, two SNPs (rs2398631 and rs72801070) moderated the association between ADHD and accumbens and amygdala volumes in adults. The significant SNPs that interacted with ADHD appear to have a role in gene expression regulation, and they are in linkage disequilibrium with NR3C1 variants that present well-characterized physiological functions. The literature-reported associations of ADHD with accumbens and amygdala were only observed for specific NR3C1 genotypes. Our findings reinforce the influence of the NR3C1 gene on subcortical volumes and ADHD. They suggest a genetic modulation of the effects of a pivotal HPA axis component in the neuroanatomical features of ADHD.
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http://dx.doi.org/10.1007/s00702-021-02425-wDOI Listing
October 2021

Analysis of structural brain asymmetries in attention-deficit/hyperactivity disorder in 39 datasets.

J Child Psychol Psychiatry 2021 10 22;62(10):1202-1219. Epub 2021 Mar 22.

Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.

Objective: Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium.

Methods: We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries.

Results: There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen's d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing.

Conclusion: Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.
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http://dx.doi.org/10.1111/jcpp.13396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455726PMC
October 2021

The neuroendocrine modulation of global DNA methylation in neuropsychiatric disorders.

Mol Psychiatry 2021 01 24;26(1):66-69. Epub 2020 Oct 24.

Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

There is an increasing body of knowledge on the influence of differential DNA methylation of specific genomic regions in psychiatric disorders. However, fewer studies have addressed global DNA methylation (GMe) levels. GMe is an estimative of biological functioning that is regulated by pervasive mechanisms able to capture the big picture of metabolic and environmental influences upon gene expression. In the present perspective article, we highlighted evidence for the relationships between cortisol and sex hormones and GMe in psychiatric disorders. We argue that the far-reaching effects of cortisol and sexual hormones on GMe may lie on the pathways linking stress and mental health. Further research on these endocrine-epigenetic links may help to explain the role of environmental stress as well as sex differences in the prevalence of psychiatric disorders.
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http://dx.doi.org/10.1038/s41380-020-00924-yDOI Listing
January 2021

Feasibility trial of the dialectical behavior therapy skills training group as add-on treatment for adults with attention-deficit/hyperactivity disorder.

J Clin Psychol 2021 03 2;77(3):516-524. Epub 2020 Sep 2.

ADHD Outpatient Program, Hospital de Clínicas de Porto Alegre, Department of Psychiatry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.

Objective: Our aim was to explore the feasibility, and efficacy of a Dialectical Behavior Therapy Skill Training Group (DBT-ST) as an add-on treatment for adult attention-deficit/hyperactivity disorder (ADHD) in Latin America.

Method: Adults with ADHD (n = 31) with stable medication treatment for ADHD and residual symptoms (ASRS > 20) were randomly assigned to DBT-ST (n = 16) or treatment as usual (TaU; n = 15) for 12 weeks. Feasibility was accessed by attendance and completion rates at 12 weeks. Efficacy outcomes were measured with the ASRS, and performed at 0, 6, 12, and 16 weeks.

Results: The DBT-ST protocol had 81.25% completion rate, with a mean attendance of 87.25% of the sessions. No significant interactions between group and time were detected for outcome measures.

Discussion: The DBT-ST was feasible as add-on treatment for adult patients with ADHD in Latin America. Replicating previous findings, DBT-ST has shown no significantly higher improvement in ADHD symptoms in comparison with TaU. Registered at the Clinical Trials database (NCT03326427).
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http://dx.doi.org/10.1002/jclp.23049DOI Listing
March 2021

Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders.

JAMA Psychiatry 2021 Jan;78(1):47-63

Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Maastricht University, the Netherlands.

Importance: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood.

Objective: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia.

Design, Setting, And Participants: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244.

Main Outcomes And Measures: Interregional profiles of group difference in cortical thickness between cases and controls.

Results: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders.

Conclusions And Relevance: In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.2694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450410PMC
January 2021

Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure.

Hum Brain Mapp 2020 May 18. Epub 2020 May 18.

Division of Psychological & Social Medicine and Developmental Neurosciences, Faculty of Medicine, Technischen Universität Dresden, Dresden, Germany.

Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case-control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case-control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.
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http://dx.doi.org/10.1002/hbm.25029DOI Listing
May 2020

Association of CHRNA5 Gene Variants with Crack Cocaine Addiction.

Neuromolecular Med 2020 09 10;22(3):384-390. Epub 2020 Mar 10.

Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

Genome-wide studies provide increasing evidence of association of genetic variants with different behaviors. However, there is a growing need for replication and subsequent characterization of specific findings. In this sense, the CHRNA5 gene has been associated with nicotine (with genome-wide significance), alcohol and cocaine addictions. So far, this gene has not been evaluated in smoked (crack) cocaine. We aimed to analyze the influence of CHRNA5 variants in crack addiction susceptibility and severity. The sample includes 300 crack-addicted patients and 769 non-addicted individuals. The CHRNA5 SNPs evaluated were rs588765, rs16969968, and rs514743. Homozygosity for rs16969968 and rs588765 major alleles was nominally associated with a risk to crack addiction (GG, P = 0.032; CC, P = 0.036, respectively). Haplotype analyses reveal significant associations (rs588765|rs16969968|rs514743 p = 7.66 × 10) and suggest a substantial role for rs16969968. These findings corroborate previous reports in cocaine addiction-in line with the expected effects of cocaine in the cholinergic system-and in the opposite direction of significant GWAS findings for nicotine addiction susceptibility. These results are strengthened by the first report of an association of rs588765 with crack addiction and by the haplotype findings. In summary, our study highlights the relevance of the α5 subunit on crack cocaine addiction, replicating previous results relating CHRNA5 with the genetics and pathophysiology of addiction of different drugs.
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http://dx.doi.org/10.1007/s12017-020-08596-1DOI Listing
September 2020

Integrative proteomics and pharmacogenomics analysis of methylphenidate treatment response.

Transl Psychiatry 2019 11 18;9(1):308. Epub 2019 Nov 18.

ADHD Outpatient Program, Adult Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.

Transcriptomics and candidate gene/protein expression studies have indicated several biological processes modulated by methylphenidate (MPH), widely used in attention-deficit/hyperactivity disorder (ADHD) treatment. However, the lack of a differential proteomic profiling of MPH treatment limits the understanding of the most relevant mechanisms by which MPH exerts its pharmacological effects at the molecular level. Therefore, our aim is to investigate the MPH-induced proteomic alterations using an experimental design integrated with a pharmacogenomic analysis in a translational perspective. Proteomic analysis was performed using the cortices of Wistar-Kyoto rats, which were treated by gavage with MPH (2 mg/kg) or saline for two weeks (n = 6/group). After functional enrichment analysis of the differentially expressed proteins (DEP) in rats, the significant biological pathways were tested for association with MPH response in adults with ADHD (n = 189) using genome-wide data. Following MPH treatment in rats, 98 DEPs were found (P < 0.05 and FC < -1.0 or > 1.0). The functional enrichment analysis of the DEPs revealed 18 significant biological pathways (gene-sets) modulated by MPH, including some with recognized biological plausibility, such as those related to synaptic transmission. The pharmacogenomic analysis in the clinical sample evaluating these pathways revealed nominal associations for gene-sets related to neurotransmitter release and GABA transmission. Our results, which integrate proteomics and pharmacogenomics, revealed putative molecular effects of MPH on several biological processes, including oxidative stress, cellular respiration, and metabolism, and extended the results involving synaptic transmission pathways to a clinical sample. These findings shed light on the molecular signatures of MPH effects and possible biological sources of treatment response variability.
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http://dx.doi.org/10.1038/s41398-019-0649-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861257PMC
November 2019

The association between SYT1-rs2251214 and cocaine use disorder further supports its role in psychiatry.

Prog Neuropsychopharmacol Biol Psychiatry 2019 08 3;94:109642. Epub 2019 May 3.

ADHD Outpatient Program, Adult Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Department of Psychiatry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. Electronic address:

Synaptotagmin-1 is an essential regulator of synaptic vesicle exocytosis, and its encoding gene (SYT1) is a genome and transcriptome-wide association hit in cognitive performance, personality and cocaine use disorder (CUD) studies. Additionally, in candidate gene studies the specific variant rs2251214 has been associated with attention-deficit/hyperactivity disorder (ADHD), antisocial personality disorder and other externalizing phenotypes in adults with ADHD, as well as with response to methylphenidate (MPH) treatment. In this context, we sought to evaluate, in an independent sample, the association of this variant with CUD, a phenotype that shares common biological underpinnings with the previously associated traits. We tested the association between SYT1-rs2251214 and CUD susceptibility and severity (addiction severity index) in a sample composed by 315 patients addicted to smoked cocaine and 769 non-addicted volunteers. SYT1-rs2251214 was significantly associated with susceptibility to CUD, where the G allele presented increased risk for the disorder in the genetic models tested (P = 0.0021, OR = 1.44, allelic; P = 0.0012, OR = 1.48, additive; P = 0.0127, OR = 1.41, dominant). This is the same allele that was associated with increased risk for ADHD and other externalizing behaviors, as well as poor response to MPH treatment in previous studies. These findings suggest that the neurotransmitter exocytosis pathway might play a critical role in the liability for psychiatric disorders, especially externalizing behaviors and CUD.
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http://dx.doi.org/10.1016/j.pnpbp.2019.109642DOI Listing
August 2019

An animal model of what? The case of spontaneously hypertensive rats.

Prog Neuropsychopharmacol Biol Psychiatry 2019 08 30;94:109617. Epub 2019 Mar 30.

Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Departamento de Psiquiatria, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. Electronic address:

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http://dx.doi.org/10.1016/j.pnpbp.2019.03.012DOI Listing
August 2019

Systematic review and meta-analysis of the behavioral effects of methylphenidate in the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder.

Neurosci Biobehav Rev 2019 05 28;100:166-179. Epub 2019 Feb 28.

ADHD Outpatient Program, Hospital de Clínicas de Porto Alegre, Brazil; Department of Psychiatry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

The spontaneously hypertensive rats (SHR) are the most widely used model for ADHD. While face and construct validity are consolidated, questions remain about the predictive validity of the SHR model. We aim at summarizing the evidence for the predictive validity of SHR by evaluating its ability to respond to methylphenidate (MPH), the most well documented treatment for ADHD. A systematic review was carried out to identify studies evaluating MPH effects on SHR behavior. Studies (n=36) were grouped into locomotion, attention, impulsivity or memory, and a meta-analysis was performed. Meta-regression, sensitivity, heterogeneity, and publication bias analyses were also conducted. MPH increased attentional and mnemonic performances in the SHR model and decreased impulsivity in a dose-dependent manner. However, MPH did not reduce hyperactivity in low and medium doses, while increased locomotor activity in high doses. Thus, since the paradoxical effect of stimulant in reducing hyperactivity was not observed in the SHR model, our study does not fully support the predictive validity of SHR, questioning their validity as an animal model for ADHD.
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http://dx.doi.org/10.1016/j.neubiorev.2019.02.019DOI Listing
May 2019

ADGRL3 rs6551665 as a Common Vulnerability Factor Underlying Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder.

Neuromolecular Med 2019 03 16;21(1):60-67. Epub 2019 Jan 16.

Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, UFRGS, Avenida Bento Gonçalves, 9500, Porto Alegre, RS, CEP: 91501-970, Brazil.

Neurodevelopmental disorders are prevalent, frequently occur in comorbidity and share substantial genetic correlation. Previous evidence has suggested a role for the ADGRL3 gene in Attention-Deficit/Hyperactivity Disorder (ADHD) susceptibility in several samples. Considering ADGRL3 functionality in central nervous system development and its previous association with neurodevelopmental disorders, we aimed to assess ADGRL3 influence in early-onset ADHD (before 7 years of age) and Autism Spectrum Disorder (ASD). The sample comprises 187 men diagnosed with early-onset ADHD, 135 boys diagnosed with ASD and 468 male blood donors. We tested the association of an ADGRL3 variant (rs6551665) with both early-onset ADHD and ASD susceptibility. We observed significant associations between ADGRL3-rs6551665 on ADHD and ASD susceptibilities; we found that G-carriers were at increased risk of ADHD and ASD, in accordance with previous studies. The overall evidence from the literature, corroborated by our results, suggests that ADGRL3 might be involved in brain development, and genetic modifications related to it might be part of a shared vulnerability factor associated with the underlying neurobiology of neurodevelopmental disorders such as ADHD and ASD.
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http://dx.doi.org/10.1007/s12017-019-08525-xDOI Listing
March 2019

Effects of DRD2 splicing-regulatory polymorphism and DRD4 48 bp VNTR on crack cocaine addiction.

J Neural Transm (Vienna) 2019 02 26;126(2):193-199. Epub 2018 Oct 26.

Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

There is evidence that dopamine receptors D2 (DRD2) and D4 (DRD4) polymorphisms may influence substance use disorders (SUD) susceptibility both individually and through their influence in the formation of DRD2-DRD4 heteromers. The dopaminergic role on the vulnerability to addiction appears to be influenced by sex. A cross-sectional study with 307 crack cocaine addicts and 770 controls was conducted. The influence of DRD2 rs2283265 and DRD4 48 bp VNTR in exon 3 variants, as well as their interaction on crack cocaine addiction susceptibility and severity were evaluated in women and men separately. An association between the DRD2 T allele and crack cocaine addiction was found in women. In this same group, interaction analysis demonstrated that the presence of DRD2-T allele and concomitant absence of DRD4-7R allele were associated with risk for crack cocaine addiction. No influence of DRD2 and DRD4 variants was observed in men regarding addiction severity. This study reinforces the role of dopaminergic genes in externalizing behaviors, especially the influence of DRD2-DRD4 interaction on SUD. This is the fourth sample that independently associated the DRD2-DRD4 interaction with SUD itself or related disorders. In addition, our findings point out to a potential difference of dopaminergic neurotransmission across sex influencing addiction susceptibility.
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http://dx.doi.org/10.1007/s00702-018-1946-5DOI Listing
February 2019

Exploring neuropsychological predictors of ADHD remission or persistence during adulthood.

Cogn Neuropsychiatry 2018 09 9;23(5):321-328. Epub 2018 Aug 9.

a Department of Psychiatry, Faculdade de Medicina , Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil.

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http://dx.doi.org/10.1080/13546805.2018.1506324DOI Listing
September 2018

Analysis of shared heritability in common disorders of the brain.

Science 2018 06;360(6395)

Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.
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http://dx.doi.org/10.1126/science.aap8757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097237PMC
June 2018

Evidence of sexual dimorphism of HTR1B gene on major adult ADHD comorbidities.

J Psychiatr Res 2017 12 8;95:269-275. Epub 2017 Sep 8.

Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; ADHD Outpatient Program, Adult Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. Electronic address:

Attention-deficit/hyperactivity disorder (ADHD) is a very common psychiatric disorder across the life cycle and frequently presents comorbidities. Since ADHD is highly heritable, several studies have focused in the underlying genetic factors involved in its etiology. One of the major challenges in this search is the phenotypic heterogeneity, which could be partly attributable to the sexual dimorphism frequently seen in psychiatric disorders. Taking into account the well-known sexual dimorphic effect observed in serotonergic system characteristics, we differentially tested the influence of HTR1B SNPs (rs11568817, rs130058, rs6296 and rs13212041) on ADHD susceptibility and on its major comorbidities according to sex. The sample comprised 564 adults with ADHD diagnosed according to DSM-IV criteria and 635 controls. There was no association of any HTR1B SNPs tested in relation to ADHD susceptibility. As for the comorbidities evaluated, after correction for multiple tests, significant associations were observed for both rs11568817 and rs130058 with substance use disorders (P = 0.009 and P = 0.018, respectively) and for rs11568817 with nicotine dependence (P = 0.025) in men with ADHD. In women with ADHD, the same rs11568817 was associated with generalized anxiety disorder (P = 0.031). The observed effects of rs11568817 G allele presence conferring risk to either substance use disorders or generalized anxiety disorder according to sex, suggest an overall scenario where a higher transcriptional activity of HTR1B, resulting from the presence of this allele, is related to externalizing behaviors in men and internalizing behaviors in women. These results are consistent with and expand previous evidence of sexual dimorphism of the serotoninergic system.
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http://dx.doi.org/10.1016/j.jpsychires.2017.09.011DOI Listing
December 2017

Further replication of the synergistic interaction between LPHN3 and the NTAD gene cluster on ADHD and its clinical course throughout adulthood.

Prog Neuropsychopharmacol Biol Psychiatry 2017 10 15;79(Pt B):120-127. Epub 2017 Jun 15.

ADHD Outpatient Program - Adult Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common and highly heritable neuropsychiatric disorder. Despite the high heritability, the unraveling of specific genetic factors related to ADHD is hampered by its considerable genetic complexity. Recent evidence suggests that gene-gene interactions can explain part of this complexity. We examined the impact of strongly supported interaction effects between the LPHN3 gene and the NTAD gene cluster (NCAM1-TTC12-ANKK1-DRD2) in a 7-year follow-up of a clinical sample of adults with ADHD, addressing associations with susceptibility, symptomatology and stability of diagnosis. The sample comprises 548 adults with ADHD and 643 controls. Entropy-based analysis indicated a potential interaction between the LPHN3-rs6551665 and TTC12-rs2303380 SNPs influencing ADHD symptom counts. Further analyses revealed significant interaction effects on ADHD total symptoms (p=0.002), and with hyperactivity/impulsivity symptom counts (p=0.005). In the group composed by predominantly hyperactive/impulsive and combined presentation, the presence of LPHN3-rs6551665 G allele was related to increased ADHD risk only in individuals carrying the TTC12-rs2303380 AA genotype (p=0.026). Also, the same allelic constellation is involved in maintenance of ADHD in a predominantly hyperactive/impulsive or combined presentation after a 7-year follow-up (p=0.008). These observations reinforce and replicate previous evidence suggesting that an interaction effect between the LPHN3 gene and the NTAD cluster may have a role in the genetic substrate associated to ADHD also in adults. Moreover, it is possible that the interactions between LPHN3 and NTAD are specific factors contributing to the development of an ADHD phenotype with increased hyperactivity/impulsivity that is maintained throughout adulthood.
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http://dx.doi.org/10.1016/j.pnpbp.2017.06.011DOI Listing
October 2017

Effects of crack cocaine addiction and stress-related genes on peripheral BDNF levels.

J Psychiatr Res 2017 07 11;90:78-85. Epub 2017 Feb 11.

Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. Electronic address:

This study examined the effects of glucocorticoid receptor (NR3C1), corticotropin-releasing hormone receptor 1 (CRHR1), and brain-derived neurotrophic factor (BDNF) genes on susceptibility to crack cocaine addiction and BDNF levels. Crack addicted patients who sought treatment (n = 280) and non-addicted individuals (n = 241) were assessed. Three SNPs in NR3C1 (rs6198, rs41423247, and rs10052957), three in CRHR1 (rs12944712, rs110402, and rs878886), and one in BDNF (rs6265) were genotyped. No significant effect was seen in the case-control analyses. Crack cocaine addicted patients showed significantly lower serum BDNF levels. Significant effects were observed for NR3C1 rs41423247 and rs10052957. These effects were restricted to non-addicted individuals and they were supported by significant gene-by-disease status interactions. For CRHR1, all SNPs were associated with BDNF levels. Although there were significant effects only in the analysis restricted to non-addicted individuals, the lack of significant results in the gene-by-disease status interaction analyses suggest a general effect on BDNF levels. The haplotype analyses presented the same effect seen in the single marker analyses. This study suggests that SNPs in the NR3C1 and CRHR1 genes may influence BDNF levels, but this effect is blunted in the context of crack cocaine addiction. Therefore, our data may be interpreted in light of several studies showing pronounced effects of crack cocaine on BDNF levels. Since peripheral BDNF is a biomarker for several psychiatric phenotypes, our results may be useful in interpreting previous associations between stress-related SNPs, drug addiction, and depression.
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http://dx.doi.org/10.1016/j.jpsychires.2017.02.011DOI Listing
July 2017

Resilience to traumatic events related to urban violence and increased IL10 serum levels.

Psychiatry Res 2017 Apr 25;250:136-140. Epub 2017 Jan 25.

Post-Graduate Program in Psychiatry and Behavioral Sciences, Federal University at Rio Grande do Sul, Brazil; Department of Psychiatry, Faculty of Medicine (FAMED), Federal University at Rio Grande do Sul, Brazil; PTSD Outpatient program (NET-Trauma), Hospital de Clínicas de Porto Alegre, Brazil. Electronic address:

The exposition to traumatic events related to urban violence is epidemic in Brazil, with rate of 80% in the general population, and is becoming a major cause of post-traumatic stress disorder (PTSD). The objective of the study was to compare serum levels of pro-inflammatory interleukin-6 (IL-6) and anti-inflammatory interleukin-10 (IL-10) in PTSD and resilient individuals. We hypothesized that resilient individuals present an attenuated pro-inflammatory and enhanced anti-inflammatory state. We conducted a case-control study comparing 30 resilient individuals and 30 PTSD patients exposed to traumatic events related to urban violence. The groups were evaluated using Self-Report Questionnaire (SRQ-20), Mini-International Neuropsychiatric Interview (MINI) and the Davidson Trauma Scale. For all individuals, blood samples were collected to determine IL-6, IL-10 and cortisol serum levels. All samples were frozen at -80°C until the assay and were analyzed with the same immunoassay kit and in duplicates. The resilient group presented higher IL-10 levels than PTSD patients [mean (CI95%); 1.03 (0.52-2.08) pg/mL vs. 0.29 (0.20-0.43) pg/mL; P=0.002]. There were no differences in terms of IL-6 or cortisol levels. The results provided evidence for increased levels of IL-10 in resilient individuals when compared to PTSD patients, probably conferring them a better anti-inflammatory response after exposition.
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http://dx.doi.org/10.1016/j.psychres.2017.01.072DOI Listing
April 2017

Predictors of persistence of ADHD into adulthood: a systematic review of the literature and meta-analysis.

Eur Child Adolesc Psychiatry 2016 Nov 28;25(11):1151-1159. Epub 2016 Mar 28.

Department of Psychiatry, ADHD Outpatient Program, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul. Rua Ramiro Barcelos, 2530-400 N., Porto Alegre, RS, 90035-009, Brazil.

Attention-deficit/hyperactivity disorder (ADHD) is traditionally conceptualized as a neurodevelopmental disorder that continues into adulthood in up to half of diagnosed cases. In light of current evidence, factors associated with the course of the disorder remain unknown. We performed a systematic review of the literature searching for risk markers from childhood that predicted the persistence of ADHD into adulthood. We reviewed 26,168 abstracts and selected 72 for full-text review. We identified data from 16 studies, comprising 6 population-based retrospective samples and 10 clinical follow-ups. We performed meta-analyses of factors evaluated by at least three studies. Severity of ADHD (OR 2.33, 95 % CI = 1.6-3.39, p < 0.001), treatment for ADHD (OR 2.09, 95 % CI = 1.04-4.18, p = 0.037), comorbid conduct disorder (OR 1.85, 95 % CI = 1.06-3.24, p = 0.030), and comorbid major depressive disorder (OR 1.8, 95 % CI = 1.1-2.95, p = 0.019) emerged as predictors already presented in childhood for ADHD persistence into adulthood. Further, we suggest that cohort studies should be designed to clarify such an important question for research and clinical practice.
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http://dx.doi.org/10.1007/s00787-016-0831-8DOI Listing
November 2016

Erratum to: Further evidence for the association between a polymorphism in the promoter region of SLC6A3/DAT1 and ADHD: findings from a sample of adults.

Eur Arch Psychiatry Clin Neurosci 2016 Dec;266(8):775-776

Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Caixa Postal: 15053, Porto Alegre, RS, 91501-970, Brazil.

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http://dx.doi.org/10.1007/s00406-016-0739-9DOI Listing
December 2016

Effects of corticotropin-releasing hormone receptor 1 SNPs on major depressive disorder are influenced by sex and smoking status.

J Affect Disord 2016 Nov 13;205:282-288. Epub 2016 Aug 13.

Department of Genetics, Institute of Biosciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; ADHD Outpatient Program, Adult Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. Electronic address:

Background: The corticotropin-releasing hormone receptor 1 (CRHR1) gene has been repeatedly implicated in Major Depressive Disorder (MDD) in humans and animal models; however, the findings are not absolutely convergent. Since recent evidence from genome-wide association studies suggests that narrowing the phenotypic heterogeneity may be crucial in genetic studies of MDD, the aim of this study was to evaluate the effects of CRHR1 polymorphisms on MDD while addressing the influence of sex and smoking status.

Methods: The association of the CRHR1 SNPs rs12944712, rs110402, and rs878886 with MDD was evaluated in 629 Brazilian adults of European descent recruited from the general population [180 (28.6%) with lifetime MDD]. The sample was subdivided according to sex and smoking status RESULTS: Among nonsmokers, there were nominal associations between MDD and all tested SNPs (rs12944712, P=0.042; rs110402, P=0.031, and rs878886, P=0.040), regardless of sex. In addition, there were significant effects of rs110402 in women (P=0.034) and rs878886 in men (P=0.013). Among lifetime smokers, there were no significant associations between CRHR1 SNPs and MDD LIMITATIONS: The lack of a depression rating scale; scarcity of information on the functionality of the CRHR1 SNPs; and relatively small sample sizes in some subgroups.

Conclusions: Our results strengthen the evidence for the role of CRHR1 SNPs in MDD susceptibility and suggest that their effects may be modulated by sex and smoking status. These findings suggest the perspective that reducing phenotypic heterogeneity is warranted in genetic studies of MDD.
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http://dx.doi.org/10.1016/j.jad.2016.08.008DOI Listing
November 2016

Meta-analysis of the DRD5 VNTR in persistent ADHD.

Eur Neuropsychopharmacol 2016 09 29;26(9):1527-1532. Epub 2016 Jul 29.

Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Department of Human Genetics, Nijmegen, The Netherlands; Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Department of Psychiatry, Nijmegen, The Netherlands. Electronic address:

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder with a complex genetic background. DRD5, the gene encoding the dopamine receptor D5, was recently confirmed as a candidate gene for ADHD in children through meta-analysis. In this study, we aimed at studying the association of the ADHD-associated variable number tandem repeat (VNTR) polymorphism upstream of DRD5 with adult ADHD. We compiled data from six sites of the International Multicentre persistent ADHD CollaboraTion (IMpACT) and reached N=6979 (3344 cases and 3635 healthy participants), the largest sample investigated so far. We tested the association of the common DRD5 alleles with categorically defined ADHD and with inattentive and hyperactive/impulsive symptom counts. Our findings provide evidence that none of the common DRD5 alleles are associated with ADHD risk or ADHD symptom counts in adults.
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http://dx.doi.org/10.1016/j.euroneuro.2016.06.012DOI Listing
September 2016

Glucocorticoid receptor gene modulates severity of depression in women with crack cocaine addiction.

Eur Neuropsychopharmacol 2016 09 7;26(9):1438-1447. Epub 2016 Jul 7.

Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. Electronic address:

Crack cocaine addicted inpatients that present more severe withdrawal symptoms also exhibit higher rates of depressive symptoms. There is strong evidence that the identification of genetic variants in depression is potentialized when reducing phenotypic heterogeneity by studying selected groups. Since depression has been associated to dysregulation of the hypothalamic-pituitary-adrenal axis, this study evaluated the effects of SNPs in stress-related genes on depressive symptoms of crack cocaine addicts at early abstinence and over the detoxification treatment (4th, 11th and 18th day post admission). Also, the role of these SNPs on the re-hospitalization rates after 2.5 years of follow-up was studied. One hundred eight-two women were enrolled and eight SNPs in four genes (NR3C2, NR3C1, FKBP5 and CRHR1) were genotyped. A significant main effect of NR3C1-rs41423247 was found, where the C minor allele increased depressive symptoms at early abstinence. This effect remained significant after 10,000 permutations to account for multiple SNPs tested (P=0.0077). There was no effect of rs41423247 on the course of detoxification treatment, but a slight effect of rs41423247 at late abstinence was detected (P=0.0463). This analysis suggests that the presence of at least one C allele is worse at early abstinence, while only CC genotype appears to increase depressive symptoms at late abstinence. Also, a slight effect of rs41423247 C minor allele increasing the number of re-hospitalizations after 2.5 years was found (P=0.0413). These findings are in agreement with previous studies reporting an influence of rs41423247 on sensitivity to glucocorticoids and further elucidate its resulting effects on depressive-related traits.
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http://dx.doi.org/10.1016/j.euroneuro.2016.06.010DOI Listing
September 2016

Crack cocaine addiction, early life stress and accelerated cellular aging among women.

Prog Neuropsychopharmacol Biol Psychiatry 2016 11 21;71:83-9. Epub 2016 Jun 21.

Developmental Cognitive Neuroscience Lab (DCNL), Biomedical Research Institute (IPB), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Brazil.

Background: Early life stress (ELS) and addiction are related to age-related diseases and telomere shortening. However, the role of telomere length (TL) in crack cocaine addiction remains unknown. The purpose of this study was to investigate the TL in a sample of crack cocaine dependent-women who reported an ELS history and in a community-based sample of elderly women as a reference group for senescence.

Methods: This study included treatment seeking crack cocaine dependents women (n=127) and elderly women without a psychiatric diagnosis (ELD, n=49). The crack cocaine sample was divided in two groups according to their Childhood Trauma Questionnaire (CTQ) scores: presence of history of childhood abuse and neglect (CRACK-ELS) and absence of ELS history (CRACK). TL was assessed by T/S ratio obtained from peripheral blood DNA using quantitative PCR assay.

Results: CRACK and CRACK-ELS subjects exhibited shortened TL in comparison to the ELD group, despite their younger age. Among crack cocaine sample, CRACK-ELS group had significantly shorter telomeres than the CRACK group. Correlation analysis within crack cocaine group indicated that TL was negatively correlated with emotional abuse scores.

Conclusions: These results support previous findings associating telomere shortening with both ELS and drug addiction. This study suggests new evidence of a distinct biological phenotype for drug-dependent women with ELS. The results support the biological senescence hypothesis underpinning ELS experience.
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http://dx.doi.org/10.1016/j.pnpbp.2016.06.009DOI Listing
November 2016

Pleiotropic effects of Chr15q25 nicotinic gene cluster and the relationship between smoking, cognition and ADHD.

J Psychiatr Res 2016 09 4;80:73-78. Epub 2016 Jun 4.

Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Adult ADHD Outpatient Clinic, Hospital de Clínicas de Porto Alegre, RS, Brazil. Electronic address:

Polymorphisms in the CHRNA5-CHRNA3-CHRNB4 gene cluster (Chr15q25) have been robustly associated with nicotine dependence, including genome-wide studies, as well as with cognitive and neuropsychological measures. In addition, cognitive processes can be influenced by nicotine use through nicotinic acetylcholine receptors (nAChRs). Here, we evaluated the effect of polymorphisms in CHRNA5-CHRNA3-CHRNB4 gene cluster and their interaction with tobacco smoking status on cognition in patients with Attention Deficit/Hyperactivity Disorder (ADHD). Eight SNPs from the CHRNA5-CHRNA3-CHRNB4 gene cluster were evaluated on a clinical sample of 403 adults with ADHD. Cognitive performance was assessed using the Wechsler Adult Intelligence Scale-Revised (WAIS-R). Analyses of covariance were used to assess the influence of single markers and their interaction with smoking status in the Vocabulary and Block Design subtests of WAIS-R. Correction for multiple comparisons was applied. Lifetime smoking was associated to Vocabulary subtest. The TT genotypes of CHRNA5 SNPs rs588765 and rs514743 showed a trend towards association with, respectively, higher and lower scores on the Vocabulary subtest. There was a significant interaction between intergenic SNP rs8023462 and smoking on Vocabulary scores. Our results are consistent with an influence of variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster on cognitive measures. The overall scenario suggests a pleiotropic role of Chr15q25 nicotinic gene cluster with complex influences in ADHD, tobacco smoking and cognitive performance, characteristics that can be partially interdependent and may share underlying genetic factors.
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http://dx.doi.org/10.1016/j.jpsychires.2016.06.002DOI Listing
September 2016

Corticosteroid receptor genes and childhood neglect influence susceptibility to crack/cocaine addiction and response to detoxification treatment.

J Psychiatr Res 2015 Sep 20;68:83-90. Epub 2015 Jun 20.

Developmental Cognitive Neuroscience Research Group (GNCD), Biomedical Research Institute (IPB), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Brazil.

The aim of this study was to analyze hypotheses-driven gene-environment and gene-gene interactions in smoked (crack) cocaine addiction by evaluating childhood neglect and polymorphisms in mineralocorticoid and glucocorticoid receptor genes (NR3C2 and NR3C1, respectively). One hundred thirty-nine crack/cocaine-addicted women who completed 3 weeks of follow-up during early abstinence composed our sample. Childhood adversities were assessed using the Childhood Trauma Questionnaire (CTQ), and withdrawal symptoms were assessed using the Cocaine Selective Severity Assessment (CSSA) scale. Conditional logistic regression with counterfactuals and generalized estimating equation modeling were used to test gene-environment and gene-gene interactions. We found an interaction between the rs5522-Val allele and childhood physical neglect, which altered the risk of crack/cocaine addiction (Odds ratio = 4.0, P = 0.001). Moreover, a NR3C2-NR3C1 interaction (P = 0.002) was found modulating the severity of crack/cocaine withdrawal symptoms. In the post hoc analysis, concomitant carriers of the NR3C2 rs5522-Val and NR3C1 rs6198-G alleles showed lower overall severity scores when compared to other genotype groups (P-values ≤ 0.035). This gene-environment interaction is consistent with epidemiological and human experimental findings demonstrating a strong relationship between early life stress and the hypothalamic-pituitary-adrenal (HPA) axis dysregulation in cocaine addiction. Additionally, this study extended in crack/cocaine addiction the findings previously reported for tobacco smoking involving an interaction between NR3C2 and NR3C1 genes.
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http://dx.doi.org/10.1016/j.jpsychires.2015.06.008DOI Listing
September 2015

Reliability and Validity of Proposed DSM-5 ADHD Symptoms in a Clinical Sample of Adults.

J Neuropsychiatry Clin Neurosci 2015 12;27(3):228-36. Epub 2015 Jun 12.

From the ADHD Outpatient Program, Hospital de Clinicas de Porto Alegre (BM, LAR, CHDB, EHG), and Dept. of Genetics, Instituto de Biociências (CHDB), Federal University of Rio Grande do Sul, Porto Alegre, Brazil; National Institute of Developmental Psychiatry for Children and Adolescents, São Paulo, Brazil (LAR); Columbia University/New York State Psychiatric Institute, New York, NY (JBT, PWF, SS); and Dept. of Psychiatry, Oregon Health and Sciences University, Portland, OR (JTN).

The DSM-5 ADHD and Disruptive Behaviors Work Group proposed two major changes for diagnosis of attention deficit hyperactivity disorder (ADHD) in adults: (1) inclusion of four new impulsivity symptoms and (2) reduction in the number of symptoms required for assigning an ADHD diagnosis. In this case-control study, the performance of these modifications was assessed in a clinical sample of 133 adult subjects (68 ADHD cases and 65 non-ADHD control subjects). The proposed new impulsivity symptoms for adults do not improve ADHD diagnosis enough to overcome potential negative effects of changing the criteria. However, fewer symptoms than the six-of-nine threshold required by DSM-IV provided the best cutoff point for identifying adults who are impaired.
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http://dx.doi.org/10.1176/appi.neuropsych.13060137DOI Listing
May 2016

NCAM1-TTC12-ANKK1-DRD2 gene cluster and the clinical and genetic heterogeneity of adults with ADHD.

Am J Med Genet B Neuropsychiatr Genet 2015 Sep 18;168(6):433-444. Epub 2015 May 18.

Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

Dysfunctions of the dopaminergic system have been implicated on the etiology of Attention Deficit/Hyperactivity Disorder (ADHD). Meta-analyses addressing the association of the dopamine receptor D2 (DRD2) gene and ADHD were inconclusive due to excessive heterogeneity across studies. Both the great phenotypic heterogeneity of ADHD and the complexity of the genomic region where DRD2 is located could contribute to the inconsistent findings. Most previous DRD2 studies focused on the well-known Taq1A (rs1800497) SNP, which is actually placed in a neighbor gene (ANKK1). These two genes, together with NCAM1 and TTC12, form the NTAD gene cluster on Chr11q22-23. In order to address the reasons for the high heterogeneity previously reported on DRD2 effects on ADHD, this study investigates the role of NTAD variants on ADHD susceptibility in adults and on the modulation of comorbidity and personality profiles in these patients. Functional polymorphisms from NTAD were analyzed, both individually and in haplotypes, on a sample of 520 adults with ADHD and 630 non-ADHD controls. No direct association of NTAD variants with ADHD susceptibility itself was observed. However, different NTAD polymorphisms and haplotypes were associated to various phenotypes relevant to the clinical heterogeneity of ADHD, including Major Depressive Disorder, Generalized Anxiety Disorder, and Harm Avoidance and Persistence temperament scores. Therefore, these findings represent a possible explanation for the multiple conflicting findings regarding polymorphisms in this genomic region in psychiatry. The NTAD cluster may comprise a variety of independent molecular influences on various brain and behavior characteristics eventually associated with ADHD comorbidities and personality traits. © 2015 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.b.32317DOI Listing
September 2015

Lack of association between the GRM7 gene and attention deficit hyperactivity disorder.

Psychiatr Genet 2014 Dec;24(6):281-2

aDepartment of Genetics, Universidade Federal do Rio Grande do Sul bInstitute for Developmental Psychiatry for Children and Adolescents cDivision of Child and Adolescent Psychiatry dAdult ADHD Outpatient Program, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul eDepartment of Psychiatry, Universidade de São Paulo, São Paulo, Brazil.

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http://dx.doi.org/10.1097/YPG.0000000000000059DOI Listing
December 2014
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