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Bruna Da Silva

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Universidade Federal de Santa Catarina - UFSC (Federal University of Santa Catarina)

Marimélia Porcionatto

Universidade Federal de São Paulo (UNIFESP)

Ana Paula Campos

UNIVERSIDADE JOSÉ DO ROSÁRIO VELLANO

Gislaine Moura-Costa

Universidade Estadual de Maringa

Maria da Graça Naffah-Mazzacoratti

Universidade Federal de São Paulo (UNIFESP)

Thiago Napoleão

Universidade Federal de Pernambuco

Armando Marques-Guedes

UNL - New University of Lisbon

Gwen Robbins Schug

University of North Carolina at Greensboro

Gabriel Gutierrez-Alonso

University of Salamanca

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Papers by Bruna Da Silva

Additional file 1: Table S1. of Screen-based sedentary behavior during adolescence and pulmonary function in a birth cohort

Crude and adjusted analyses of average cumulative sedentary behavior from 11 to 18 years of age a... more

epitope3D: a machine learning method for conformational B-cell epitope prediction

Briefings in Bioinformatics, 2021

The ability to identify antigenic determinants of pathogens, or epitopes, is fundamental to guide... more The ability to identify antigenic determinants of pathogens, or epitopes, is fundamental to guide rational vaccine development and immunotherapies, which are particularly relevant for rapid pandemic response. A range of computational tools has been developed over the past two decades to assist in epitope prediction; however, they have presented limited performance and generalization, particularly for the identification of conformational B-cell epitopes. Here, we present epitope3D, a novel scalable machine learning method capable of accurately identifying conformational epitopes trained and evaluated on the largest curated epitope data set to date. Our method uses the concept of graph-based signatures to model epitope and non-epitope regions as graphs and extract distance patterns that are used as evidence to train and test predictive models. We show epitope3D outperforms available alternative approaches, achieving Mathew’s Correlation Coefficient and F1-scores of 0.55 and 0.57 on cr...

SU1ANDROGEN Receptor Signaling Pathways Influence in Attention-Deficit/Hyperactivity Disorder

European Neuropsychopharmacology, 2019

Exocytosis-Related Gene-Sets and Response to Methylphenidate Treatment in Adults with Adhd

European Neuropsychopharmacology, 2019

response is heritable, but genome-wide association studies of common variants have failed to find... more response is heritable, but genome-wide association studies of common variants have failed to find consistent signals. Since patients with TRD occupy the extreme end of the treatment response distribution, they may also carry alleles that occupy an extreme of frequency and functional impact. Methods: Study participants included 146 unrelated patients, 130 with MDD or bipolar TRD and 16 with good response to antidepressants, drawn from several sources. All participants had experienced at least two failed antidepressant trials not explained by non-adherence or severe comorbidities. Exomes were captured with various arrays and sequenced by use of Illumina or SOLiD platforms. Variants were called and assessed for quality using the GATK best practices pipeline. Results: After quality control, 348,077 variants were identified, of which 99,711 were exonic and had allele frequencies o1% in ExAC. We sought to remove false positives by filtering out variants that were not found in dbSNP, appeared in only one individual, or had missing genotypes in all typical responders. Functional filtering of variants that were called as synonymous or non-frameshift left 4,456 qualifying variants in 3,370 genes. Very few qualifying variants were found in 41 TRD patient, but LIST GENES each carried the same qualifying variant in 42 individuals. A total of 820 genes carried at least 2 qualifying variants. This set of genes was tested for overlap with genes implicated in MDD (Hyde et al., 2016) or antidepressant treatment response (GENDEP, MARS, and STARn D Investigators, 2013). Significant excess overlap of genes was detected for both MDD (OR= 1.5, p = 0.035) and response to 2 wks of antidepressant treatment (OR= 2.16; P = 1 Â 10-5). The latter gene set was enriched for "actin cytoskeleton" by ENRICHR (q = 0.01). Discussion: Some of the same genes implicated in MDD or antidepressant treatment response through common variants may also harbor rare, functional variants in patients with TRD. Further study of these genes could yield new insights into the pathophysiology of treatment-resistant depression.

Low birthweight and preterm birth: trends and inequalities in four population-based birth cohorts in Pelotas, Brazil, 1982-2015

International journal of epidemiology, Jan 22, 2018

Despite positive changes in most maternal risk factors in Brazil, previous studies did not show r... more Despite positive changes in most maternal risk factors in Brazil, previous studies did not show reductions in preterm birth and low birthweight. We analysed trends and inequalities in these outcomes over a 33-year period in a Brazilian city. Four population-based birth cohort studies were carried out in the city of Pelotas in 1982, 1993, 2004 and 2015, with samples ranging from 4231 to 5914 liveborn children. Low birthweight (LBW) was defined as <2500 g, and preterm birth as less than 37 weeks of gestation. Information was collected on family income, maternal skin colour and other risk factors for low birthweight. Multivariable linear regression was used to estimate the contribution of risk factors to time trends in birthweight. Preterm births increased from 5.8% (1982) to 13.8% (2015), and LBW prevalence increased from 9.0% to 10.1%, being higher for boys and for children born to mothers with low income and brown or black skin colour. Mean birthweight remained stable, around 320...

Social inequalities in mental disorders and substance misuse in young adults : A birth cohort study in Southern Brazil

Social psychiatry and psychiatric epidemiology, Jan 2, 2018

To investigate the association between mental disorders and substance misuse at 30 years of age w... more To investigate the association between mental disorders and substance misuse at 30 years of age with gender, socioeconomic position at birth, and family income trajectories. The 1982 Pelotas Birth Cohort was used; all 5914 children born alive at hospital were originally enrolled (99.2% of all city births). In 2012, 3701 subjects were located and interviewed (68% retention rate). Mental disorders and substance misuse were assessed, and their prevalence analysed according to gender, socioeconomic status at birth, and four different income trajectories: always poor, never poor, poor at birth/non-poor at age 30, and non-poor at birth/poor at age 30. While women presented higher prevalence of mental disorders, substance misuse was much more frequent among men. Individuals in the lowest income quintile at birth presented 2-5 times more mental disorders and substance misuse than those in the highest quintile. Young adults who were always poor or were not poor at birth but were poor at 30 y...

Integrative genomic analysis of methylphenidate response in attention-deficit/hyperactivity disorder

Scientific reports, Jan 30, 2018

Methylphenidate (MPH) is the most frequently used pharmacological treatment in children with atte... more Methylphenidate (MPH) is the most frequently used pharmacological treatment in children with attention-deficit/hyperactivity disorder (ADHD). However, a considerable interindividual variability exists in clinical outcome. Thus, we performed a genome-wide association study of MPH efficacy in 173 ADHD paediatric patients. Although no variant reached genome-wide significance, the set of genes containing single-nucleotide polymorphisms (SNPs) nominally associated with MPH response (P < 0.05) was significantly enriched for candidates previously studied in ADHD or treatment outcome. We prioritised the nominally significant SNPs by functional annotation and expression quantitative trait loci (eQTL) analysis in human brain, and we identified 33 SNPs tagging cis-eQTL in 32 different loci (referred to as eSNPs and eGenes, respectively). Pathway enrichment analyses revealed an over-representation of genes involved in nervous system development and function among the eGenes. Categories relat...

P3.07-008 METASTATIC NSCLC: Treatment Reality from 182 Cases of Lung Adenocarcinoma in a Brazilian Public Cancer Health Service

Journal of Thoracic Oncology, 2017

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

Journal of Psychiatric Research, 2017

Attention-deficit/hyperactivity disorder (ADHD) is a very common and highly heritable psychiatric... more Attention-deficit/hyperactivity disorder (ADHD) is a very common and highly heritable psychiatric disorder and frequently presents psychiatric comorbidities. One of the major challenges in the search for genetic factors is the phenotypic heterogeneity, which could be partly attributable to the sexual dimorphism frequently seen in psychiatric disorders but not easily amenable to analyses in association studies, especially GWAS. Taking into account the well-known sexual dimorphic effect observed in serotonergic system characteristics, we 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 Brazilian adults of European descent 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. Regarding the comorbidities evaluated, after correction for multiple tests, significant associations were observed for both rs11568817 and rs130058 with substance use disorders (P corr = 0.009 and P corr = 0.018, respectively) and for rs11568817 with nicotine dependence (P corr = 0.025) in men with ADHD. In women with ADHD, the same rs11568817 was associated with generalized anxiety disorder (P corr = 0.031). The observed effects of rs11568817 G allele replicate previous meta-analyses findings, adding the perspective of sexual dimorphic effects. The overall scenario suggests that 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 serotonergic system.

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

Progress in neuro-psychopharmacology & biological psychiatry, Oct 14, 2017

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common and highly heritable neuropsychiatric... more 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 gro...

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

Journal of psychiatric research, Jul 11, 2017

This study examined the effects of glucocorticoid receptor (NR3C1), corticotropin-releasing hormo... more 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 ...

Replicated association of Synaptotagmin (SYT1) with ADHD and its broader influence in externalizing behaviors

European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, Mar 24, 2017

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder, affecting both ... more Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder, affecting both children and adults. The Soluble N-ethylmaleimide sensitive factor Attachment REceptors (SNARE) complex has been implicated in ADHD pathophysiology since it is a key component of neurotransmitter release events and neurodevelopment processes, and SNPs in this complex have been associated with ADHD. Here we aim to analyze the effects of SNARE complex variants on ADHD susceptibility and its clinical heterogeneity in affected adults. We tested the association between ADHD and polymorphisms on the SNARE genes STX1A (rs2228607), SYT1 (rs1880867 and rs2251214), VAMP2 (26bp Ins/Del) and SNAP25 (rs6108461 and rs8636) on a sample comprised of 548 adults with ADHD and 644 non-affected controls. Regarding clinical heterogeneity, we further investigated the effects of associated SNPs on age at onset of impairment due to ADHD and on relevant externalizing behaviors (i.e. school suspensions/expulsions...

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

European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, Sep 7, 2016

Crack cocaine addicted inpatients that present more severe withdrawal symptoms also exhibit highe... more 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 af...

SNARE complex in developmental psychiatry: neurotransmitter exocytosis and beyond

Journal of neural transmission (Vienna, Austria : 1996), Aug 8, 2016

Multiple biological processes throughout development require intracellular vesicular trafficking,... more Multiple biological processes throughout development require intracellular vesicular trafficking, where the SNARE (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptors) complex plays a major role. The core proteins forming the SNARE complex are SNAP-25 (synaptosomal-associated protein 25), VAMP (vesicle-associated membrane protein) and Syntaxins, besides its regulatory proteins, such as Synaptotagmin. Genes encoding these proteins (SNAP25, VAMP1, VAMP2, STX1A, SYT1 and SYT2) have been studied in relation to psychiatric disorders susceptibility. Here, we review physiological aspects of SNARE complex and genetic association results reported for attention deficit hyperactivity disorder, both in children and adults, autism spectrum disorders, major depressive disorder, bipolar disorder and schizophrenia. Moreover, we included findings from expression, pharmacogenetics and animal model studies regarding these clinical phenotypes. The overall scenario depict...

Controle de vacina��o de crian�as matriculadas em escolas municipais da cidade de S�o Paulo

Rev Esc Enferm Usp, 2007

The influence on DNA damage of glycaemic parameters, oral antidiabetic drugs and polymorphisms of genes involved in the DNA repair system

Mutagenesis, 2013

The hyperglycaemia seen in type 2 diabetes mellitus (DM2) is associated with increased oxidative ... more The hyperglycaemia seen in type 2 diabetes mellitus (DM2) is associated with increased oxidative stress and production of reactive oxygen species, both of which are factors that can provoke DNA damage. Notwithstanding, other factors, including medications and individual susceptibility, can also induce this type of DNA lesion. The objective of this study was, therefore, to investigate the influence of glycaemic control, oral antidiabetic drugs (metformin and glibenclamide) and polymorphisms of the XRCC1 and XRCC3 genes on the frequency of DNA damage in DM2 patients, which was accessed by the cytokinesisblock micronucleus cytome and the comet assays on the ex vivo mitogenically stimulated lymphocytes. The 53 people recruited to take part in the study were already on treatment with metformin and were followed for 5 months. Ten of these patients were put on combined treatment with the addition of glibenclamide. It was observed that the greater the plasma metformin concentration, the lower the frequency of micronuclei (MN) in the sample total (P = 0.009) and also that the subset of patients using combined treatment including glibenclamide had a significantly higher MN rate 90 days after starting combined treatment (P = 0.024). In the subset who only took metformin, the rate of MN was significantly higher among carriers of the 399Gln allele on the XRCC1 gene (P = 0.008). In addition, homozygotes for the 241Thr allele exhibited a significant increase in MN in the combined treatment group (P = 0.008). Our results suggest that different combinations of oral antidiabetic drugs and polymorphisms on genes involved in the DNA damage repair system could influence the frequency of this type of chromosome lesion, which can be a useful biomarker for assessing the risk of developing cancer.

Additional file 1: Table S1. of Screen-based sedentary behavior during adolescence and pulmonary function in a birth cohort

Crude and adjusted analyses of average cumulative sedentary behavior from 11 to 18 years of age a... more

epitope3D: a machine learning method for conformational B-cell epitope prediction

Briefings in Bioinformatics, 2021

The ability to identify antigenic determinants of pathogens, or epitopes, is fundamental to guide... more The ability to identify antigenic determinants of pathogens, or epitopes, is fundamental to guide rational vaccine development and immunotherapies, which are particularly relevant for rapid pandemic response. A range of computational tools has been developed over the past two decades to assist in epitope prediction; however, they have presented limited performance and generalization, particularly for the identification of conformational B-cell epitopes. Here, we present epitope3D, a novel scalable machine learning method capable of accurately identifying conformational epitopes trained and evaluated on the largest curated epitope data set to date. Our method uses the concept of graph-based signatures to model epitope and non-epitope regions as graphs and extract distance patterns that are used as evidence to train and test predictive models. We show epitope3D outperforms available alternative approaches, achieving Mathew’s Correlation Coefficient and F1-scores of 0.55 and 0.57 on cr...

SU1ANDROGEN Receptor Signaling Pathways Influence in Attention-Deficit/Hyperactivity Disorder

European Neuropsychopharmacology, 2019

Exocytosis-Related Gene-Sets and Response to Methylphenidate Treatment in Adults with Adhd

European Neuropsychopharmacology, 2019

response is heritable, but genome-wide association studies of common variants have failed to find... more response is heritable, but genome-wide association studies of common variants have failed to find consistent signals. Since patients with TRD occupy the extreme end of the treatment response distribution, they may also carry alleles that occupy an extreme of frequency and functional impact. Methods: Study participants included 146 unrelated patients, 130 with MDD or bipolar TRD and 16 with good response to antidepressants, drawn from several sources. All participants had experienced at least two failed antidepressant trials not explained by non-adherence or severe comorbidities. Exomes were captured with various arrays and sequenced by use of Illumina or SOLiD platforms. Variants were called and assessed for quality using the GATK best practices pipeline. Results: After quality control, 348,077 variants were identified, of which 99,711 were exonic and had allele frequencies o1% in ExAC. We sought to remove false positives by filtering out variants that were not found in dbSNP, appeared in only one individual, or had missing genotypes in all typical responders. Functional filtering of variants that were called as synonymous or non-frameshift left 4,456 qualifying variants in 3,370 genes. Very few qualifying variants were found in 41 TRD patient, but LIST GENES each carried the same qualifying variant in 42 individuals. A total of 820 genes carried at least 2 qualifying variants. This set of genes was tested for overlap with genes implicated in MDD (Hyde et al., 2016) or antidepressant treatment response (GENDEP, MARS, and STARn D Investigators, 2013). Significant excess overlap of genes was detected for both MDD (OR= 1.5, p = 0.035) and response to 2 wks of antidepressant treatment (OR= 2.16; P = 1 Â 10-5). The latter gene set was enriched for "actin cytoskeleton" by ENRICHR (q = 0.01). Discussion: Some of the same genes implicated in MDD or antidepressant treatment response through common variants may also harbor rare, functional variants in patients with TRD. Further study of these genes could yield new insights into the pathophysiology of treatment-resistant depression.

Low birthweight and preterm birth: trends and inequalities in four population-based birth cohorts in Pelotas, Brazil, 1982-2015

International journal of epidemiology, Jan 22, 2018

Despite positive changes in most maternal risk factors in Brazil, previous studies did not show r... more Despite positive changes in most maternal risk factors in Brazil, previous studies did not show reductions in preterm birth and low birthweight. We analysed trends and inequalities in these outcomes over a 33-year period in a Brazilian city. Four population-based birth cohort studies were carried out in the city of Pelotas in 1982, 1993, 2004 and 2015, with samples ranging from 4231 to 5914 liveborn children. Low birthweight (LBW) was defined as <2500 g, and preterm birth as less than 37 weeks of gestation. Information was collected on family income, maternal skin colour and other risk factors for low birthweight. Multivariable linear regression was used to estimate the contribution of risk factors to time trends in birthweight. Preterm births increased from 5.8% (1982) to 13.8% (2015), and LBW prevalence increased from 9.0% to 10.1%, being higher for boys and for children born to mothers with low income and brown or black skin colour. Mean birthweight remained stable, around 320...

Social inequalities in mental disorders and substance misuse in young adults : A birth cohort study in Southern Brazil

Social psychiatry and psychiatric epidemiology, Jan 2, 2018

To investigate the association between mental disorders and substance misuse at 30 years of age w... more To investigate the association between mental disorders and substance misuse at 30 years of age with gender, socioeconomic position at birth, and family income trajectories. The 1982 Pelotas Birth Cohort was used; all 5914 children born alive at hospital were originally enrolled (99.2% of all city births). In 2012, 3701 subjects were located and interviewed (68% retention rate). Mental disorders and substance misuse were assessed, and their prevalence analysed according to gender, socioeconomic status at birth, and four different income trajectories: always poor, never poor, poor at birth/non-poor at age 30, and non-poor at birth/poor at age 30. While women presented higher prevalence of mental disorders, substance misuse was much more frequent among men. Individuals in the lowest income quintile at birth presented 2-5 times more mental disorders and substance misuse than those in the highest quintile. Young adults who were always poor or were not poor at birth but were poor at 30 y...

Integrative genomic analysis of methylphenidate response in attention-deficit/hyperactivity disorder

Scientific reports, Jan 30, 2018

Methylphenidate (MPH) is the most frequently used pharmacological treatment in children with atte... more Methylphenidate (MPH) is the most frequently used pharmacological treatment in children with attention-deficit/hyperactivity disorder (ADHD). However, a considerable interindividual variability exists in clinical outcome. Thus, we performed a genome-wide association study of MPH efficacy in 173 ADHD paediatric patients. Although no variant reached genome-wide significance, the set of genes containing single-nucleotide polymorphisms (SNPs) nominally associated with MPH response (P < 0.05) was significantly enriched for candidates previously studied in ADHD or treatment outcome. We prioritised the nominally significant SNPs by functional annotation and expression quantitative trait loci (eQTL) analysis in human brain, and we identified 33 SNPs tagging cis-eQTL in 32 different loci (referred to as eSNPs and eGenes, respectively). Pathway enrichment analyses revealed an over-representation of genes involved in nervous system development and function among the eGenes. Categories relat...

P3.07-008 METASTATIC NSCLC: Treatment Reality from 182 Cases of Lung Adenocarcinoma in a Brazilian Public Cancer Health Service

Journal of Thoracic Oncology, 2017

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

Journal of Psychiatric Research, 2017

Attention-deficit/hyperactivity disorder (ADHD) is a very common and highly heritable psychiatric... more Attention-deficit/hyperactivity disorder (ADHD) is a very common and highly heritable psychiatric disorder and frequently presents psychiatric comorbidities. One of the major challenges in the search for genetic factors is the phenotypic heterogeneity, which could be partly attributable to the sexual dimorphism frequently seen in psychiatric disorders but not easily amenable to analyses in association studies, especially GWAS. Taking into account the well-known sexual dimorphic effect observed in serotonergic system characteristics, we 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 Brazilian adults of European descent 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. Regarding the comorbidities evaluated, after correction for multiple tests, significant associations were observed for both rs11568817 and rs130058 with substance use disorders (P corr = 0.009 and P corr = 0.018, respectively) and for rs11568817 with nicotine dependence (P corr = 0.025) in men with ADHD. In women with ADHD, the same rs11568817 was associated with generalized anxiety disorder (P corr = 0.031). The observed effects of rs11568817 G allele replicate previous meta-analyses findings, adding the perspective of sexual dimorphic effects. The overall scenario suggests that 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 serotonergic system.

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

Progress in neuro-psychopharmacology & biological psychiatry, Oct 14, 2017

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common and highly heritable neuropsychiatric... more 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 gro...

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

Journal of psychiatric research, Jul 11, 2017

This study examined the effects of glucocorticoid receptor (NR3C1), corticotropin-releasing hormo... more 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 ...

Replicated association of Synaptotagmin (SYT1) with ADHD and its broader influence in externalizing behaviors

European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, Mar 24, 2017

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder, affecting both ... more Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder, affecting both children and adults. The Soluble N-ethylmaleimide sensitive factor Attachment REceptors (SNARE) complex has been implicated in ADHD pathophysiology since it is a key component of neurotransmitter release events and neurodevelopment processes, and SNPs in this complex have been associated with ADHD. Here we aim to analyze the effects of SNARE complex variants on ADHD susceptibility and its clinical heterogeneity in affected adults. We tested the association between ADHD and polymorphisms on the SNARE genes STX1A (rs2228607), SYT1 (rs1880867 and rs2251214), VAMP2 (26bp Ins/Del) and SNAP25 (rs6108461 and rs8636) on a sample comprised of 548 adults with ADHD and 644 non-affected controls. Regarding clinical heterogeneity, we further investigated the effects of associated SNPs on age at onset of impairment due to ADHD and on relevant externalizing behaviors (i.e. school suspensions/expulsions...

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

European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, Sep 7, 2016

Crack cocaine addicted inpatients that present more severe withdrawal symptoms also exhibit highe... more 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 af...

SNARE complex in developmental psychiatry: neurotransmitter exocytosis and beyond

Journal of neural transmission (Vienna, Austria : 1996), Aug 8, 2016

Multiple biological processes throughout development require intracellular vesicular trafficking,... more Multiple biological processes throughout development require intracellular vesicular trafficking, where the SNARE (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptors) complex plays a major role. The core proteins forming the SNARE complex are SNAP-25 (synaptosomal-associated protein 25), VAMP (vesicle-associated membrane protein) and Syntaxins, besides its regulatory proteins, such as Synaptotagmin. Genes encoding these proteins (SNAP25, VAMP1, VAMP2, STX1A, SYT1 and SYT2) have been studied in relation to psychiatric disorders susceptibility. Here, we review physiological aspects of SNARE complex and genetic association results reported for attention deficit hyperactivity disorder, both in children and adults, autism spectrum disorders, major depressive disorder, bipolar disorder and schizophrenia. Moreover, we included findings from expression, pharmacogenetics and animal model studies regarding these clinical phenotypes. The overall scenario depict...

Controle de vacina��o de crian�as matriculadas em escolas municipais da cidade de S�o Paulo

Rev Esc Enferm Usp, 2007

The influence on DNA damage of glycaemic parameters, oral antidiabetic drugs and polymorphisms of genes involved in the DNA repair system

Mutagenesis, 2013

The hyperglycaemia seen in type 2 diabetes mellitus (DM2) is associated with increased oxidative ... more The hyperglycaemia seen in type 2 diabetes mellitus (DM2) is associated with increased oxidative stress and production of reactive oxygen species, both of which are factors that can provoke DNA damage. Notwithstanding, other factors, including medications and individual susceptibility, can also induce this type of DNA lesion. The objective of this study was, therefore, to investigate the influence of glycaemic control, oral antidiabetic drugs (metformin and glibenclamide) and polymorphisms of the XRCC1 and XRCC3 genes on the frequency of DNA damage in DM2 patients, which was accessed by the cytokinesisblock micronucleus cytome and the comet assays on the ex vivo mitogenically stimulated lymphocytes. The 53 people recruited to take part in the study were already on treatment with metformin and were followed for 5 months. Ten of these patients were put on combined treatment with the addition of glibenclamide. It was observed that the greater the plasma metformin concentration, the lower the frequency of micronuclei (MN) in the sample total (P = 0.009) and also that the subset of patients using combined treatment including glibenclamide had a significantly higher MN rate 90 days after starting combined treatment (P = 0.024). In the subset who only took metformin, the rate of MN was significantly higher among carriers of the 399Gln allele on the XRCC1 gene (P = 0.008). In addition, homozygotes for the 241Thr allele exhibited a significant increase in MN in the combined treatment group (P = 0.008). Our results suggest that different combinations of oral antidiabetic drugs and polymorphisms on genes involved in the DNA damage repair system could influence the frequency of this type of chromosome lesion, which can be a useful biomarker for assessing the risk of developing cancer.