Publications by authors named "Mara H Hutz"

125 Publications

Diagnostic prediction model for levodopa-induced dyskinesia in Parkinson's disease.

Arq Neuropsiquiatr 2020 04;78(4):206-216

Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Neurociências e Ciências Comportamentais, Ribeirão Preto SP, Brazil.

Background: There are currently no methods to predict the development of levodopa-induced dyskinesia (LID), a frequent complication of Parkinson's disease (PD) treatment. Clinical predictors and single nucleotide polymorphisms (SNP) have been associated to LID in PD.

Objective: To investigate the association of clinical and genetic variables with LID and to develop a diagnostic prediction model for LID in PD.

Methods: We studied 430 PD patients using levodopa. The presence of LID was defined as an MDS-UPDRS Part IV score ≥1 on item 4.1. We tested the association between specific clinical variables and seven SNPs and the development of LID, using logistic regression models.

Results: Regarding clinical variables, age of PD onset, disease duration, initial motor symptom and use of dopaminergic agonists were associated to LID. Only CC genotype of ADORA2A rs2298383 SNP was associated to LID after adjustment. We developed two diagnostic prediction models with reasonable accuracy, but we suggest that the clinical prediction model be used. This prediction model has an area under the curve of 0.817 (95% confidence interval [95%CI] 0.77‒0.85) and no significant lack of fit (Hosmer-Lemeshow goodness-of-fit test p=0.61).

Conclusion: Predicted probability of LID can be estimated with reasonable accuracy using a diagnostic clinical prediction model which combines age of PD onset, disease duration, initial motor symptom and use of dopaminergic agonists.
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http://dx.doi.org/10.1590/0004-282X20190191DOI Listing
April 2020

Identification of environmental and genetic factors that influence warfarin time in therapeutic range.

Genet Mol Biol 2020 10;43(1 suppl 2):e20190025. Epub 2020 Feb 10.

Universidade Federal do Rio Grande do Sul, Departamento de Genética, Porto Alegre, RS, Brazil.

Warfarin is an oral anticoagulant prescribed to prevent and treat thromboembolic disorders. It has a narrow therapeutic window and must have its effect controlled. Prothrombin test, expressed in INR value, is used for dose management. Time in therapeutic range (TTR) is an important outcome of quality control of anticoagulation therapy and is influenced by several factors. The aim of this study was to identify genetic, demographic, and clinical factors that can potentially influence TTR. In total,422 patients using warfarin were investigated. Glibenclamide co-medication and presence of CYP2C9*2 and/or *3 alleles were associated with higher TTR, while amiodarone, acetaminophen and verapamil co-medication were associated with lower TTR. Our data suggest that TTR is influenced by co-medication and genetic factors. Thus, individuals in use of glibenclamide may need a more careful monitoring and genetic testing (CYP2C9*2 and/or *3 alleles) may improve the anticoagulation management. In addition, in order to reach and maintain the INR in the target for a longer period, it is better to discuss dose adjustment in office instead of by telephone assessment. Other studies are needed to confirm these results and to find more variables that could contribute to this important parameter.
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http://dx.doi.org/10.1590/1678-4685-GMB-2019-0025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198020PMC
February 2020

The Role of in Shared Susceptibility of Psychiatric Disorders during Childhood: A Population-Based Birth Cohort Study.

Genes (Basel) 2019 08 20;10(8). Epub 2019 Aug 20.

Departamento de Medicina Preventiva, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo 01246-903, Brasil.

Background: It has been suggested that microRNAs (miRNAs; short non-protein-coding RNA molecules that mediate post-transcriptional regulation), including mir-9 and mir-34 families, are important for brain development. Current data suggest that mir-9 and mir-34 may have shared effects across psychiatric disorders. This study aims to explore the role of genetic polymorphisms in the (rs4916723) and (rs4938723) genes on the susceptibility of psychiatric disorders in children from the 2004 Pelotas Birth Cohort.

Methods: Psychiatric disorders were assessed in 3585 individuals using Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), criteria through the application of standard semi-structured interviews (using the Development and Well-Being Assessment, DAWBA) at the six-years-of-age follow-up. The outcome was defined as the presence of any mental disorder. We also considered two broad groups of internalizing and externalizing disorders to further investigate the role of these variants in mental health.

Results: We observed an association between rs4916723 () and the presence of any psychiatric disorder (odds ratios (OR) = 0.820; 95% CI = 0.7130-0.944; = 0.006) and a suggestive effect on internalizing disorders (OR = 0.830; 95% CI = 0.698-0.987; = 0.035). rs4938723 () was not associated with any evaluated outcome.

Conclusion: The study suggests that may have an important role on a broad susceptibility for psychiatric disorders and may be important mainly for internalization problems.
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http://dx.doi.org/10.3390/genes10080626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723948PMC
August 2019

NUDT15 Polymorphism in Native American Populations of Brazil.

Clin Pharmacol Ther 2019 06 21;105(6):1321-1322. Epub 2019 Mar 21.

Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brasil.

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http://dx.doi.org/10.1002/cpt.1379DOI Listing
June 2019

Polymorphisms in Attention-Deficit/Hyperactivity Disorder (ADHD): Further Evidence Linking Sleep and Circadian Disturbances and ADHD.

Genes (Basel) 2019 01 28;10(2). Epub 2019 Jan 28.

Federal University of Pelotas, Post-Graduate Program in Epidemiology, Pelotas 96020-220, Brazil.

Circadian and sleep disorders, short sleep duration, and evening chronotype are often present in attention-deficit/hyperactivity disorder (ADHD). , considered the master gene in the circadian rhythm, has been explored by few studies. Understanding the relationship between ADHD and may provide additional information to understand the correlation between ADHD and sleep problems. In this study, we aimed to explore the association between ADHD and , using several genetic markers to comprehensively cover the gene extension. A total of 259 ADHD children and their parents from a Brazilian clinical sample were genotyped for eight single nucleotide polymorphisms (SNPs) in the locus. We tested the individual markers and the haplotype effects using binary logistic regression. Binary logistic and linear regressions considering ADHD symptoms among ADHD cases were conducted as secondary analysis. As main result, the analysis showed a risk effect of the G-A-T-G-G-C-G-A (rs534654, rs1801260, rs6855837, rs34897046, rs11931061, rs3817444, rs4864548, rs726967) haplotype on ADHD. A suggestive association between ADHD and rs534654 was observed. The results suggest that the genetic susceptibility to circadian rhythm attributed to the gene may play an important role on ADHD.
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http://dx.doi.org/10.3390/genes10020088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410065PMC
January 2019

The future of pharmacogenetics in Parkinson's disease treatment.

Pharmacogenomics 2018 02 1;19(3):171-174. Epub 2017 Dec 1.

Serviço de Neurologia, Hospital de Clínicas de Porto Alegre, Porto Alegre, 90035-903, Brazil.

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http://dx.doi.org/10.2217/pgs-2017-0180DOI Listing
February 2018

SLCO1A2, SLCO1B1 and SLCO2B1 polymorphisms influences chloroquine and primaquine treatment in Plasmodium vivax malaria.

Pharmacogenomics 2017 Oct 4;18(15):1393-1400. Epub 2017 Oct 4.

Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

Aim: The association of transporters gene polymorphisms with chloroquine/primaquine malaria treatment response was investigated in a Brazilian population.

Patients & Methods: Totally, 164 Plasmodium vivax malaria infected patients were included. Generalized estimating equations were performed to determine gene influences on parasitemia and/or gametocytemia clearance over treatment time.

Results: Significant interaction between SLCO2B1 genotypes and treatment over time for parasitemia clearance rate on day 2 were observed (p = 0.002). SLCO1A2 and SLCO1B1 gene treatment over time interactions were associated with gametocytemia clearance rate (p = 0.018 and p = 0.024). ABCB1, ABCC4 and SLCO1B3 were not associated with treatment response.

Conclusion: The present work presents the first pharmacogenetic report of an association between chloroquine/primaquine responses with OATP transporters.
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http://dx.doi.org/10.2217/pgs-2017-0077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099631PMC
October 2017

Tumor necrosis factor alpha polymorphisms are associated with Parkinson's disease age at onset.

Neurosci Lett 2017 Sep 24;658:133-136. Epub 2017 Aug 24.

Departamento de Genética, Universidade Federal do Rio Grande do Sul, Brazil. Electronic address:

The role of neuroinflammation in Parkinson's disease (PD) has been demonstrated through several different approaches. It was suggested an inflammation-derived oxidative stress and cytokine-dependent toxicity role in the nigrostriatal pathway degeneration and hasten progression of disease. Tumor necrosis factor alpha (TNFA) gene promoter polymorphisms might alter the expression of this cytokine contributing to the pro- and anti-inflammatory polarization. An increased TNFA expression might lead to inflammatory profile predominance. The aim of study was to determine if TNFA haplotypes are associated with PD age at onset. Five polymorphisms in TNFA gene were investigated in 226 patients with idiopathic PD in relation to age at onset. Haplotype grouping was based on allele expression. Logistic binary regression analysis showed that the genetic background leading to higher TNF-α expression confers a higher risk to develop PD earlier. Gender and ancestry did not differ between groups. High TNFA expression may contribute for faster dopaminergic neuron degeneration. In this context, a higher genetic pro-inflammatory profile confers a higher risk to develop PD earlier.
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http://dx.doi.org/10.1016/j.neulet.2017.08.049DOI Listing
September 2017

The dopamine transporter role in psychiatric phenotypes.

Am J Med Genet B Neuropsychiatr Genet 2018 03 2;177(2):211-231. Epub 2017 Aug 2.

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

The dopamine transporter (DAT) is one of the most relevant and investigated neurotransmitter transporters. DAT is a plasma membrane protein which plays a homeostatic role, controlling both extracellular and intracellular concentrations of dopamine (DA). Since unbalanced DA levels are known to be involved in numerous mental disorders, a wealth of investigations has provided valuable insights concerning DAT role into normal brain functioning and pathological processes. Briefly, this extensive but non-systematic review discusses what is recently known about the role of SLC6A3 gene which encodes the dopamine transporter in psychiatric phenotypes. DAT protein, SLC6A3 gene, animal models, neuropsychology, and neuroimaging investigations are also concisely discussed. To conclude, current challenges are reviewed in order to provide perspectives for future studies.
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http://dx.doi.org/10.1002/ajmg.b.32578DOI Listing
March 2018

Association between DNA methyltransferase gene polymorphism and Parkinson's disease.

Neurosci Lett 2017 02 29;639:146-150. Epub 2016 Dec 29.

Postgraduate Program in Health Sciences, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil. Electronic address:

Parkinson's disease (PD) is a common and complex neurodegenerative disorder, the second most prevalent, only behind Alzheimer's disease. Recent studies suggest that environmental factors may contribute for neurodegeneration through induction of epigenetic modifications, such as DNA methylation, that is carried out by enzymes, such as DNMT1 and DNMT3B. This present study targeted to investigate the association among DNMT1 and DNMT3B polymorphisms with PD. Five hundred and twenty-two participants (214 PD patients following UK Brain Bank criteria and 308 healthy individuals) were evaluated. DNA was obtained from whole blood and genotypes were detected by an allelic discrimination assay using TaqMan MGB probes on a real-time PCR system. The polymorphisms studied were rs2162560 and rs759920 (DNMT1) and rs2424913, rs998382 and rs2424932 (DNMT3B). Was found association between DNMT3B rs2424913 in T allele carriers with PD. The presence of the T allele was associated with PD (OR=1.80, 95% CI 1.16-2.81, p=0.009). No significant difference was observed for others DNMT3B SNPs. Also, no association between PD and the control group were observed for DNMT1 polymorphisms. This is the first study addressing an association between DNMT3B polymorphism and PD. The polymorphism may play a role in the pathogenesis of PD.
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http://dx.doi.org/10.1016/j.neulet.2016.12.058DOI Listing
February 2017

The effect of SNPs in CYP450 in chloroquine/primaquine Plasmodium vivax malaria treatment.

Pharmacogenomics 2016 Nov 21;17(17):1903-1911. Epub 2016 Oct 21.

Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

Background: Chloroquine/primaquine is the current therapy to eliminate Plasmodium vivax infection in the Amazon region.

Aims: This study investigates CYP1A2, CYP2C8, CYP2C9, CYP3A4 and CYP3A5 genetic polymorphisms influence on cloroquine/primaquine treatment.

Patients & Methods: Generalized estimating equations analyses were performed to determine the genetic influence in parasitemia and/or gametocytemia clearance over treatment time in 164 patients.

Results: An effect of CYP2C8 low-activity alleles on treatment was observed (p = 0.01). From baseline to first day of treatment, wild-type individuals achieved greater reduction of gametocytes than low-activity allele carriers. CYP2C9 and CYP3A5 genes showed a trend for gametocytemia and parasitemia clearance rates.

Conclusion: Future studies should be performed to access the extent of CYP2C8, CYP2C9 and CYP3A5 gene polymorphisms influence on cloroquine/primaquine treatment.
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http://dx.doi.org/10.2217/pgs-2016-0131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099632PMC
November 2016

and genes are associated with hyperactivity and inattention traits in the 1993 Pelotas Birth Cohort: evidence of sex-specific combined effect.

J Psychiatry Neurosci 2016 10;41(6):405-412

From the Department of Genetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil (Akutagava-Martins, Salatino-Oliveira, Genro, Hutz); the Child and Adolescent Psychiatry Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil (Kieling, Rohde); the Department of Psychiatry, Universidade de São Paulo, São Paulo, São Paulo, Brazil (Polanczyk); the Graduate Program in Epidemiology, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil (Anselmi, Menezes, Gonçalves, Wehrmeister, Barros); the Graduate Program in Health and Behavior, Universidade Católica de Pelotas, Pelotas, Rio Grande do Sul, Brazil (Barros); the Department of Statistics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil (Callegari-Jacques); and the Institute for Developmental Psychiatry for Children and Adolescents (INCT-CNPq), Brazil (Polanczyk, Rohde).

Background: Attention-deficit/hyperactivity disorder (ADHD) symptoms are dimensionally distributed in the population. This study aimed to assess the role of the catechol-O-methyltransferase () and of the dopamine transporter () genes on ADHD symptoms in the general population.

Methods: We investigated 4101 individuals from the 1993 Pelotas Birth Cohort Study using the parent version of the Strengths and Difficulties Questionnaire (SDQ) at ages 11 and 15 years. The SDQ hyperactivity/inattention scores were the main outcomes.

Results: Linear regression analyses demonstrated that the increasing number of 158Val and 10R alleles significantly predicted increasing SDQ hyperactivity/inattention scores in boys at both 11 and 15 years of age (β coefficient = 0.049, = 2.189, = 0.029, = 0.012, and β coefficient = 0.064, = 2.832, = 0.005, = 0.008, respectively). The presence of both 158Val and 10R alleles was also associated with full categorical ADHD diagnosis at 18 years of age in boys (χ = 4.561, = 0.033, odds ratio 2.473, 95% confidence interval 1.048-5.838) from this cohort. We did not observe these associations in girls.

Limitations: Our analyses of SDQ hyperactivity/inattention scores were not corrected for SDQ scores of conduct problems because these variables were highly correlated.

Conclusion: This study demonstrates a role for and genes on hyperactivity/inattention symptoms and provides further support for ADHD as the extreme of traits that vary in the population. It also confirms previous evidence for sexual dimorphism on and gene expression.
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http://dx.doi.org/10.1503/jpn.150270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082511PMC
October 2016

The effects of old and recent migration waves in the distribution of HBB*S globin gene haplotypes.

Genet Mol Biol 2016 Oct-Dec;39(4):515-523. Epub 2016 Oct 3.

Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

Sickle cell hemoglobin is the result of a mutation at the sixth amino acid position of the beta (β) globin chain. The HBB*S gene is in linkage disequilibrium with five main haplotypes in the β-globin-like gene cluster named according to their ethnic and geographic origins: Bantu (CAR), Benin (BEN), Senegal (SEN), Cameroon (CAM) and Arabian-Indian (ARAB). These haplotypes demonstrated that the sickle cell mutation arose independently at least five times in human history. The distribution of βS haplotypes among Brazilian populations showed a predominance of the CAR haplotype. American populations were clustered in two groups defined by CAR or BEN haplotype frequencies. This scenario is compatible with historical records about the slave trade in the Americas. When all world populations where the sickle cell gene occurs were analyzed, three clusters were disclosed based on CAR, BEN or ARAB haplotype predominance. These patterns may change in the next decades due to recent migrations waves. Since these haplotypes show different clinical characteristics, these recent migrations events raise the necessity to develop optimized public health programs for sickle cell disease screening and management.
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http://dx.doi.org/10.1590/1678-4685-GMB-2016-0032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127156PMC
October 2016

GAD1 gene polymorphisms are associated with hyperactivity in Attention-Deficit/Hyperactivity Disorder.

Am J Med Genet B Neuropsychiatr Genet 2016 12 17;171(8):1099-1104. Epub 2016 Aug 17.

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

Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders of childhood. Recent studies suggest a role for γ-aminobutyric acid (GABA) on ADHD hyperactive/impulsive symptoms due to behavioral disinhibition resulting from inappropriate modulation of both glutamatergic and GABAergic signaling. The glutamic acid decarboxylase (GAD1) gene encodes a key enzyme of GABA biosynthesis. The aim of the present study was to investigate the possible influence of GAD1 SNPs rs3749034 and rs11542313 on ADHD susceptibility. The clinical sample consisted of 547 families with ADHD probands recruited at the ADHD Outpatient Clinics from Hospital de Clínicas de Porto Alegre. Hyperactive/impulsive symptoms were evaluated based on parent reports from the Swanson, Nolan, and Pelham Scale-version IV (SNAP-IV). The C allele of rs11542313 was significantly overtransmitted from parents to ADHD probands (P = 0.02). Hyperactive/impulsive score was higher in rs3749034G allele (P = 0.005, Cohen's D = 0.19) and rs11542313C allele (P = 0.03; Cohen's D = 0.16) carriers. GAD1 haplotypes were also associated with higher hyperactive/impulsive scores in ADHD youths (global P-value = 0.01). In the specific haplotype test, the GC haplotype was the one with the highest hyperactive/impulsive scores (P = 0.03). Our results suggest that the GAD1 gene is associated with ADHD susceptibility, contributing particularly to the hyperactive/impulsive symptom domain. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.b.32489DOI Listing
December 2016

The role of variants from the innate immune system genes in tuberculosis and skin test response in a Native American population.

Hum Immunol 2016 Oct 23;77(10):981-984. Epub 2016 Jun 23.

Departamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. Electronic address:

Native American populations show higher tuberculosis (TB) mortality and infectivity rates than non-Native populations. Variants in the innate immune system seem to have an important role on TB susceptibility. The role of some innate immune system variants in TB susceptibility and/or skin test response (PPD) were investigated in the Aché, a Native American population. Complement receptor 1 and toll like receptor 9 variants were associated with anergy to PPD and protection to TB, respectively. These findings demonstrate an important role of the innate immune system variants in TB susceptibility.
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http://dx.doi.org/10.1016/j.humimm.2016.06.017DOI Listing
October 2016

High Frequency of Hb E-Saskatoon (HBB: c.67G > A) in Brazilians: A New Genetic Origin?

Hemoglobin 2016 Aug 2;40(4):228-30. Epub 2016 Jun 2.

b Departamento de Genética , Instituto de Biociências, Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil.

Hb E-Saskatoon [β22(B4)Glu→Lys, HBB: c.67G > A] is a rare, nonpathological β-globin variant that was first described in a Canadian woman of Scottish and Dutch ancestry and has since then been detected in several populations. The aim of the present study was to identify the origin of Hb E-Saskatoon in Brazil using β-globin haplotypes and genetic ancestry in carriers of this hemoglobin (Hb) variant. Blood samples were investigated by isoelectric focusing (IEF) and high performance liquid chromatography (HPLC) using commercial kits. Hb E-Saskatoon was confirmed by amplification of the HBB gene, followed by sequence analysis. Haplotypes of the β-globin gene were determined by polymerase chain reaction (PCR), followed by digestion with specific restriction enzymes. Individual ancestry was estimated with 48 biallelic insertion/deletions using three 16-plex PCR amplifications. The IEF pattern was similar to Hbs C (HBB: c.19G > A) and Hb E (HBB: c.79G > A) [isoelectric point (pI): 7.59-7.65], and HPLC results showed an elution in the Hb S (HBB: c.20A > T) window [retention time (RT): 4.26-4.38]. DNA sequencing of the amplified β-globin gene showed a mutation at codon 22 (GAA>AAA) corresponding to Hb E-Saskatoon. A total of 11 cases of this variant were identified. In nine unrelated individuals, Hb E-Saskatoon was in linkage disequilibrium with haplotype 2 [+ - - - -]. All subjects showed a high degree of European contribution (mean = 0.85). Hb E-Saskatoon occurred on the β-globin gene of haplotype 2 in all Brazilian carriers. These findings suggest a different genetic origin for this Hb variant from that previously described.
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http://dx.doi.org/10.1080/03630269.2016.1189433DOI Listing
August 2016

The role of protein intrinsic disorder in major psychiatric disorders.

Am J Med Genet B Neuropsychiatr Genet 2016 09 17;171(6):848-60. Epub 2016 May 17.

Department of Genetics, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.

Although new candidate genes for Autism Spectrum Disorder (ASD), Schizophrenia (SCZ), Attention-Deficit/Hyperactivity Disorder (ADHD), and Bipolar Disorder (BD) emerged from genome-wide association studies (GWAS), their underlying molecular mechanisms remain poorly understood. Evidences of the involvement of intrinsically disordered proteins in diseases have grown in the last decade. These proteins lack tridimensional structure under physiological conditions and are involved in important cellular functions such as signaling, recognition and regulation. The aim of the present study was to identify the role and abundance of intrinsically disordered proteins in a set of psychiatric diseases and to test whether diseases are different regarding protein intrinsic disorder. Our hypothesis is that differences across psychiatric illnesses phenotypes and symptoms may arise from differences in intrinsic protein disorder content and properties of each group. A bioinformatics prediction of intrinsic disorder was performed in proteins retrieved based on top findings from GWAS, Copy Number Variation and candidate gene investigations for each disease. This approach revealed that about 80% of studied proteins presented long stretches of disorder. This amount was significantly higher than that observed in general eukaryotic proteins, and those involved in cardiovascular diseases. These results suggest that proteins with intrinsic disorder are a common feature of neurodevelopment and synaptic transmission processes which are potentially involved in the etiology of psychiatric diseases. Moreover, we identified differences between ADHD and ASD when the binary prediction of structure and putative binding sites were compared. These differences may be related to variation in symptom complexity between both diseases. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.b.32455DOI Listing
September 2016

Influence of genetic, biological and pharmacological factors on levodopa dose in Parkinson's disease.

Pharmacogenomics 2016 Apr 29;17(5):481-8. Epub 2016 Mar 29.

Departamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

Aim: Levodopa is first-line treatment of Parkinson's disease motor symptoms but, dose response is highly variable. Therefore, the aim of this study was to determine how much levodopa dose could be explained by biological, pharmacological and genetic factors.

Patients & Methods: A total of 224 Parkinson's disease patients were genotyped for SV2C and SLC6A3 polymorphisms by allelic discrimination assays. Comedication, demographic and clinical data were also assessed.

Results: All variables with p < 0.20 were included in a multiple regression analysis for dose prediction. The final model explained 23% of dose variation (F = 11.54; p < 0.000001).

Conclusion: Although a good prediction model was obtained, it still needs to be tested in an independent sample to be validated.
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http://dx.doi.org/10.2217/pgs.15.183DOI Listing
April 2016

NOS1 and SNAP25 polymorphisms are associated with Attention-Deficit/Hyperactivity Disorder symptoms in adults but not in children.

J Psychiatr Res 2016 Apr 18;75:75-81. Epub 2016 Jan 18.

Department of Genetics, Universidade Federal do Rio Grande do Sul, Brazil. Electronic address:

Several investigations documented that Attention-Deficit/Hyperactivity Disorder (ADHD) is better conceptualized as a dimensional disorder. At the same time, the disorder seems to have different neurobiological underpinnings and phenotypic presentation in children compared to adults. Neurodevelopmental genes could explain, at least partly these differences. The aim of the present study was to examine possible associations between polymorphisms in SNAP25, MAP1B and NOS1 genes and ADHD symptoms in Brazilian samples of children/adolescents and adults with ADHD. The youth sample consisted of 301 patients whereas the adult sample comprises 485 individuals with ADHD. Diagnoses of ADHD and comorbidities were based on the Diagnostic and Statistical Manual of Mental Disorders-4th edition criteria. The Swanson, Nolan and Pelham Scale-Version IV (SNAP-IV) was applied by psychiatrists blinded to genotype. The total SNAP-IV scores were compared between genotypes. Impulsivity SNAP-IV scores were also compared according to NOS1 genotypes. Adult patients homozygous for the C allele at SNAP25 rs8636 showed significantly higher total SNAP-IV scores (F = 11.215; adjusted P-value = 0.004). Impulsivity SNAP-IV scores were also significantly different according to NOS1 rs478597 polymorphisms in adults with ADHD (F = 6.282; adjusted P-value = 0.026). These associations were not observed in children and adolescents with ADHD. These results suggest that SNAP25 and NOS1 genotypes influence ADHD symptoms only in adults with ADHD. Our study corroborates previous evidences for differences in the genetic contribution to adult ADHD compared with childhood ADHD.
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http://dx.doi.org/10.1016/j.jpsychires.2016.01.010DOI Listing
April 2016

Val66Met BDNF polymorphism is associated with Parkinson's disease cognitive impairment.

Neurosci Lett 2016 Feb 21;615:88-91. Epub 2016 Jan 21.

Departamento de Genética, Universidade Federal do Rio Grande do Sul, Brazil. Electronic address:

Parkinson's disease (PD) is one of the most common neurodegenerative diseases worldwide. Besides characteristic PD motor features, the disease has important non-motor characteristics such as cognitive impairment. The role of genetic factors in cognitive impairment associated with PD is still unclear. In this study, we examined whether BDNF Val66Met was associated with impaired cognition in Parkinson's disease. One hundred and seventy five patients with a clinical diagnosis of Parkinson's disease were included. Global cognitive abilities of the patients were measured by the Mini-Mental State Examination (MMSE). Poisson Regression models were used to test for association between 66Met carriers and cognitive impairment controlling for covariates. Carriers of at least one BDNF 66Met allele presented a higher prevalence of cognitive impairment (p=0.005 RR=1.45 IC=95% [1.1-1.8]). These results suggest a role for BDNF Val66Met polymorphism on cognitive impairment in PD.
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http://dx.doi.org/10.1016/j.neulet.2016.01.030DOI Listing
February 2016

High interpopulation homogeneity in Central Argentina as assessed by Ancestry Informative Markers (AIMs).

Genet Mol Biol 2015 Jul-Sep;38(3):324-31. Epub 2015 Aug 21.

Departamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

The population of Argentina has already been studied with regard to several genetic markers, but much more data are needed for the appropriate definition of its genetic profile. This study aimed at investigating the admixture patterns and genetic structure in Central Argentina, using biparental markers and comparing the results with those previously obtained by us with mitochondrial DNA (mtDNA) in the same samples. A total of 521 healthy unrelated individuals living in 13 villages of the Córdoba and San Luis provinces were tested. The individuals were genotyped for ten autosomal ancestry informative markers (AIMs). Allele frequencies were compared with those of African, European and Native American populations, chosen to represent parental contributions. The AIM estimates indicated a greater influence of the Native American ancestry as compared to previous studies in the same or other Argentinean regions, but smaller than that observed with the mtDNA tests. These differences can be explained, respectively, by different genetic contributions between rural and urban areas, and asymmetric gene flow occurred in the past. But a most unexpected finding was the marked interpopulation genetic homogeneity found in villages located in diverse geographic environments across a wide territory, suggesting considerable gene flow.
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http://dx.doi.org/10.1590/S1415-475738320140260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612595PMC
October 2015

Gene-Environment Interaction in Youth Depression: Replication of the 5-HTTLPR Moderation in a Diverse Setting.

Am J Psychiatry 2015 Oct 28;172(10):978-85. Epub 2015 Aug 28.

From the Department of Psychiatry, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Brazil; the Department of Genetics, Universidade Federal do Rio Grande do Sul, Brazil; the Department of Basic Health Sciences. Universidade Federal de Ciências da Saúde de Porto Alegre; the Department of Psychiatry, Universidade de São Paulo, Brazil; the Center of Mathematics Computation and Cognition, Universidade Federal do ABC, Brazil; the Postgraduate Program in Epidemiology, Universidade Federal de Pelotas, Brazil; and the National Institute for Developmental Psychiatry for Children and Adolescents, Brazil.

Objective: Replication of scientific findings is a major challenge in biomedical research. In psychiatry, the identification of measured gene-environment interactions (G×E) has promoted a heated debate over the past decade, with controversial results about its influence on disorders such as major depression. The authors sought to replicate a 2003 study on G×E in youth depression in a large birth cohort from a diverse setting.

Method: Using data from the 1993 Pelotas Birth Cohort Study, and adopting a design as similar as possible to that of the original study, the authors tested whether the relationship between childhood maltreatment and a subsequent depressive episode diagnosis was moderated by 5-HTTLPR genotype. Of 5,249 individuals assessed at birth and followed up to age 18, data on the evaluation for depressive episodes in early adulthood, on childhood maltreatment, and on genotype were available for 3,558 participants, of whom 2,392 remained after conservative screening for previous depressive symptoms. Associations were investigated with logistic regression analyses and controlling for potential confounders.

Results: The results replicated important findings of the original study, this time in a sample of young adults from a middle-income country: there was a differential dose-response relationship between childhood maltreatment and major depression according to 5-HTTLPR genotype.

Conclusions: After following a research strategy as comparable as possible to that of the original study, the results corroborated the existence of a measured G×E, now in a large sample from a different sociocultural context. These findings provide further evidence that a genetic variant in the 5-HTTLPR moderates the link between childhood maltreatment and youth depression.
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http://dx.doi.org/10.1176/appi.ajp.2015.14070896DOI Listing
October 2015

Genome-wide association study of warfarin maintenance dose in a Brazilian sample.

Pharmacogenomics 2015 12;16(11):1253-63. Epub 2015 Aug 12.

Pharmacology Division, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.

Aim: Extreme discordant phenotype and genome-wide association (GWA) approaches were combined to explore the role of genetic variants on warfarin dose requirement in Brazilians.

Methods: Patients receiving low (≤ 20 mg/week; n = 180) or high stable warfarin doses (≥ 42.5 mg/week; n = 187) were genotyped with Affymetrix Axiom(®) Biobank arrays. Imputation was carried out using data from the combined 1000 Genomes project.

Results: Genome-wide signals (p ≤ 5 × 10(-8)) were identified in the well-known VKORC1 (lead SNP, rs749671; OR: 20.4; p = 1.08 × 10(-33)) and CYP2C9 (lead SNP, rs9332238, OR: 6.8 and p = 4.4 × 10(-13)) regions. The rs9332238 polymorphism is in virtually perfect LD with CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910). No other genome-wide significant regions were identified in the study.

Conclusion: We confirmed the important role of VKORC1 and CYP2C9 polymorphisms in warfarin dose. Original submitted 14 January 2015; Revision submitted 26 May 2015.
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http://dx.doi.org/10.2217/PGS.15.73DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573240PMC
June 2016

MAP1B and NOS1 genes are associated with working memory in youths with attention-deficit/hyperactivity disorder.

Eur Arch Psychiatry Clin Neurosci 2016 Jun 2;266(4):359-66. Epub 2015 Aug 2.

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

Diverse efforts have been done to improve the etiologic understanding of mental disorders, such as attention-deficit/hyperactivity disorder (ADHD). It becomes clear that research in mental disorders needs to move beyond descriptive syndromes. Several studies support recent theoretical models implicating working memory (WM) deficits in ADHD complex neuropsychology. The aim of this study was to examine the association between rs2199161 and rs478597 polymorphisms at MAP1B and NOS1 genes with verbal working memory in children and adolescents with ADHD. A total of 253 unrelated ADHD children/adolescents were included. The sample was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders-4th edition criteria. Digit Span from the Wechsler Intelligence Scale for Children-Third Edition was used to assess verbal WM. The raw scores from both forward and backward conditions of Digit Span were summed and converted into scaled scores according to age. The means of scaled Digit Span were compared according to genotypes by ANOVA. Significant differences in Digit Span scores between MAP1B genotype groups (rs2199161: F = 5.676; p = 0.018) and NOS1 (rs478597: F = 6.833; p = 0.009) genes were detected. For both polymorphisms, the CC genotype carriers showed a worse performance in WM task. Our findings suggest possible roles of NOS1 and MAP1B genes in WM performance in ADHD patients, replicating previous results with NOS1 gene in this cognitive domain in ADHD children.
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http://dx.doi.org/10.1007/s00406-015-0626-9DOI Listing
June 2016

Is there a role for ADORA2A polymorphisms in levodopa-induced dyskinesia in Parkinson's disease patients?

Pharmacogenomics 2015 15;16(6):573-82. Epub 2015 Apr 15.

Departmento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Caixa postal 15053, Porto Alegre, RS, 91501-970, Brazil.

Aim: Levodopa is first line treatment of Parkinson's disease (PD). However, its use is associated with the presence of motor fluctuations and dyskinesias. In recent years, adenosine A2A receptor (A2AR) is rising as a therapeutic target for PD. The aim of the present study was to investigate whether ADORA2A is associated with levodopa adverse effects.

Patients & Methods: Two hundred and eight PD patients on levodopa therapy were investigated. rs2298383 and rs3761422 at the ADORA2A gene were genotyped by allelic discrimination assays.

Results: A trend for association was observed for both polymorphism and diplotypes with dyskinesia.

Conclusion: The present results should be considered as positive preliminary evidence. Further studies are needed to determine the association between ADORA2A and dyskinesia. Original submitted 3 December 2014; Revision submitted 13 February 2015.
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http://dx.doi.org/10.2217/pgs.15.23DOI Listing
February 2016

The lactase persistence genotype is a protective factor for the metabolic syndrome.

Genet Mol Biol 2014 Oct 21;37(4):611-5. Epub 2014 Oct 21.

Departamento de Genética , Universidade Federal do Rio Grande do Sul , Porto Alegre, RS , Brazil .

The Metabolic Syndrome (MetS) is defined as a pattern of metabolic disturbances, which include central obesity, insulin resistance and hyperglycemia, dyslipidemia, and hypertension. Milk has been promoted as a healthy beverage that can improve the management of MetS. Most human adults, however, down-regulate the production of intestinal lactase after weaning. Lactase encoded by the LCT gene is necessary for lactose digestion. The -13910C > T SNP (rs4988235) is responsible for the lactase persistence phenotype in European populations. We herein investigated whether the lactase persistence genotype is also associated with the MetS in subjects from a Brazilian population of European descent. This study consisted of 334 individuals (average age of 41 years) genotyped by PCR-based methods for the -13910C > T SNP. Clinical data were assessed and the genotypes were tested for their independent contribution to the MetS using chi-square tests and multiple logistic regression analysis. Univariate analyses showed that hypertension and MetS prevalence were higher in individuals with the lactase non-persistence genotype than in lactase persistence subjects. Furthermore, lactase persistence was associated with a lower risk for MetS (OR = 0.467; 95% CI 0.264-0.824; p = 0.009). These results suggest that LCT genotypes can be a valuable tool for the management of MetS treatment.
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http://dx.doi.org/10.1590/S1415-47572014005000012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4261958PMC
October 2014

PPARA gene and phenprocoumon: a new predictor of response variability.

Pharmacogenet Genomics 2015 Feb;25(2):93-5

aDepartment of Genetics, Federal University of Rio Grande do Sul bRio Grande do Sul Cardiology Institute, Cardiology University Foundation cCardiology Division, Porto Alegre Clinics Hospital, Porto Alegre, Rio Grande do Sul, Brazil.

Phenprocoumon is an anticoagulant used for thromboembolic disorder prophylaxis metabolized mainly by CYP3A4. However, polymorphisms in this gene did not explain the observed variability. PPARA (peroxisome proliferator-activated receptor-α) is a nuclear receptor that, among others, influences CYP3A4 gene expression. The aim of this study was to determine whether PPARA gene polymorphisms and the CYP3A4*22 allele are associated with phenprocoumon dose variability. A total of 198 patients on a stable dose of phenprocoumon were included in the study. Genotyping was performed by allele discrimination using standardized TaqMan assays. Differences between the average phenprocoumon dose and genotypes/haplotypes were assessed by analysis of variance and multiple linear regression analyses. Patients with the PPARA rs4253728A allele needed higher phenprocoumon doses. However, the effect size (3%) of this association was small. The CYP3A4*22 allele was not associated with the dose of phenprocoumon. As this is the first report of an association between PPARA gene polymorphisms and phenprocoumon dose, future studies are warranted to confirm these results.
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http://dx.doi.org/10.1097/FPC.0000000000000109DOI Listing
February 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

Distribution of CYP2D6 alleles and phenotypes in the Brazilian population.

PLoS One 2014 20;9(10):e110691. Epub 2014 Oct 20.

Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.

The CYP2D6 enzyme is one of the most important members of the cytochrome P450 superfamily. This enzyme metabolizes approximately 25% of currently prescribed medications. The CYP2D6 gene presents a high allele heterogeneity that determines great inter-individual variation. The aim of this study was to evaluate the variability of CYP2D6 alleles, genotypes and predicted phenotypes in Brazilians. Eleven single nucleotide polymorphisms and CYP2D6 duplications/multiplications were genotyped by TaqMan assays in 1020 individuals from North, Northeast, South, and Southeast Brazil. Eighteen CYP2D6 alleles were identified in the Brazilian population. The CYP2D6*1 and CYP2D6*2 alleles were the most frequent and widely distributed in different geographical regions of Brazil. The highest number of CYPD6 alleles observed was six and the frequency of individuals with more than two copies ranged from 6.3% (in Southern Brazil) to 10.2% (Northern Brazil). The analysis of molecular variance showed that CYP2D6 is homogeneously distributed across different Brazilian regions and most of the differences can be attributed to inter-individual differences. The most frequent predicted metabolic status was EM (83.5%). Overall 2.5% and 3.7% of Brazilians were PMs and UMs respectively. Genomic ancestry proportions differ only in the prevalence of intermediate metabolizers. The IM predicted phenotype is associated with a higher proportion of African ancestry and a lower proportion of European ancestry in Brazilians. PM and UM classes did not vary among regions and/or ancestry proportions therefore unique CYP2D6 testing guidelines for Brazilians are possible and could potentially avoid ineffective or adverse events outcomes due to drug prescriptions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110691PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203818PMC
June 2015

Parkinson's disease pharmacogenomics: new findings and perspectives.

Pharmacogenomics 2014 Jun;15(9):1253-71

Departamento de Genética, Instituto de Biociências, UFRGS, Caixa Postal 15053, 91501-970, Porto Alegre, RS, Brazil.

Parkinson's disease (PD) is unique among neurodegenerative disorders because a highly effective pharmacological symptomatic treatment is available. The marked variability in drug response and in adverse profiles associated with this treatment led to the search of genetic markers associated with these features. We present a review of the literature on PD pharmacogenetics to provide a critical discussion of the current findings, new approaches, limitations and recommendations for future research. Pharmacogenetics studies in this field have assessed several outcomes and genes, with special focus on dopaminergic genes, mainly DRD2, which is the most important receptor in nigrostriatal pathway. The heterogeneity in methodological strategies employed by different studies is impressive. The question of whether PD pharmacogenetics studies will improve clinical management by causing a shift from a trial-and-error approach to a pharmacological regimen that takes into account the individual variability remains an open question. Collaborative longitudinal studies with larger sample sizes, better outcome definitions and replication studies are required.
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http://dx.doi.org/10.2217/pgs.14.93DOI Listing
June 2014