RESUMEN

SERPINA6 and SERPINA1 were recently identified as the main genes associated with plasma cortisol concentration in humans. Although dysregulation in the Hypothalamus-Pituitary-Adrenal (HPA) axis has been observed in Attention Deficit/Hyperactivity Disorder (ADHD), the molecular mechanisms underlying this relationship are still unclear. Evaluation of the SERPINA6/SERPINA1 gene cluster in ADHD may provide relevant information to uncover them. We tested the association between the SERPINA6/SERPINA1 locus, including 95 single nucleotide polymorphisms (SNPs), and ADHD, using data from a Brazilian clinical sample of 259 ADHD probands and their parents. The single SNP association was tested using binary logistic regression, and we performed Classification and Regression Tree (CART) analysis to evaluate genotype combinations' effects on ADHD susceptibility. We assessed SNPs' regulatory effects through the Genotype-Tissue Expression (GTEx) v8 tool, and performed a complementary look-up analysis in the largest ADHD GWAS to date. There was a suggestive association between ADHD and eight variants located in the SERPINA6 region and one in the intergenic region between SERPINA6 and SERPINA1 after correction for multiple tests (p < 0.032). CART analysis showed that the combined effects of genotype GG in rs2144833 and CC in rs10129500 were associated with ADHD (OR = 1.78; CI95% = 1.24-2.55). The GTEx assigned the SNPs as eQTLs for genes in different tissues, including SERPINA6, and the look-up analysis revealed two SNPs associated with ADHD. These results suggest a shared genetic component between cortisol levels and ADHD. HPA dysregulation/altered stress response in ADHD might be mediated by upregulation of corticosteroid binding globulin (CBG, encoded by SERPINA6) expression.

Asunto(s)

Trastorno por Déficit de Atención con Hiperactividad , Transcortina , alfa 1-Antitripsina , Trastorno por Déficit de Atención con Hiperactividad/genética , Brasil , Marcadores Genéticos , Genotipo , Humanos , Hidrocortisona/metabolismo , Polimorfismo de Nucleótido Simple , Transcortina/genética , alfa 1-Antitripsina/genética

RESUMEN

OBJECTIVES: To evaluate the shared genetic components, common pathways and causal relationship between ADHD and sleep-related phenotypes. METHODS: We used the largest genome-wide association summary statistics available for attention-deficit/hyperactivity disorder (ADHD) and various sleep-related phenotypes (insomnia, napping, daytime dozing, snoring, ease getting up, daytime sleepiness, sleep duration and chronotype). We estimated the genomic correlation using cross-trait linkage disequilibrium score regression (LDSR) and investigated the potential common mechanisms using gene-based cross-trait metanalyses and functional enrichment analyses. The causal effect was estimated using two-sample Mendelian randomisation (TSMR), using the inverse variance weighted method as the main estimator. RESULTS: A positive genomic correlation between insomnia, daytime napping, daytime dozing, snoring, daytime sleepiness, short and long sleep duration, and ADHD was observed. Insomnia, daytime sleepiness, and snoring shared genes with ADHD, that are involved in neurobiological functions and regulatory signalling pathways. The TSMR supported a causal effect of insomnia, daytime napping, and short sleep duration on ADHD, and of ADHD on long sleep duration and chronotype. CONCLUSION: Comorbidity between sleep phenotypes and ADHD may be mediated by common genetic factors that play an important role in neuronal signalling pathways. A causal effect of sleep disturbances and short sleep duration on ADHD reinforced their role as predictors of ADHD.

Asunto(s)

Trastorno por Déficit de Atención con Hiperactividad , Trastornos del Sueño-Vigilia , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/genética , Comorbilidad , Estudio de Asociación del Genoma Completo , Humanos , Fenotipo , Factores de Riesgo , Sueño/genética , Trastornos del Sueño-Vigilia/epidemiología , Trastornos del Sueño-Vigilia/genética

RESUMEN

Circadian and sleep disorders, short sleep duration, and evening chronotype are often present in attention-deficit/hyperactivity disorder (ADHD). CLOCK, considered the master gene in the circadian rhythm, has been explored by few studies. Understanding the relationship between ADHD and CLOCK 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 CLOCK, 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 CLOCK 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 CLOCK gene may play an important role on ADHD.

Asunto(s)

Trastorno por Déficit de Atención con Hiperactividad/genética , Proteínas CLOCK/genética , Polimorfismo de Nucleótido Simple , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Niño , Ritmo Circadiano , Femenino , Humanos , Masculino , Sueño

RESUMEN

The circadian clock system drives daily rhythms in physiology, metabolism, and behavior in mammals. Molecular mechanisms of this system consist of multiple clock genes, with Circadian Locomotor Output Cycles Kaput (CLOCK) as a core member that plays an important role in a wide range of behaviors. Alterations in the CLOCK gene are associated with common psychiatric disorders as well as with circadian disturbances comorbidities. This review addresses animal, molecular, and genetic studies evaluating the role of the CLOCK gene on many psychiatric conditions, namely autism spectrum disorder, schizophrenia, attention-deficit/hyperactivity disorder, major depressive disorder, bipolar disorder, anxiety disorder, and substance use disorder. Many animal experiments focusing on the effects of the Clock gene in behavior related to psychiatric conditions have shown consistent biological plausibility and promising findings. In humans, genetic and gene expression studies regarding disorder susceptibility, sleep disturbances related comorbidities, and response to pharmacological treatment, in general, are in agreement with animal studies. However, the number of controversial results is high. Literature suggests that the CLOCK gene exerts important influence on these conditions, and influences the susceptibility to phenotypes of psychiatric disorders.

Asunto(s)

Proteínas CLOCK/genética , Trastornos Mentales/genética , Animales , Proteínas CLOCK/fisiología , Relojes Circadianos/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genómica/métodos , Humanos , Trastornos Mentales/fisiopatología , Modelos Animales , Polimorfismo de Nucleótido Simple

RESUMEN

BACKGROUND: The 5-HTT gene contains polymorphisms in its promoter region, the insertion/deletion (5-HTTLPR) that creates long (L) or short (S) alleles (biallelic approach) and SNP (rs25531) in L allele (triallelic approach). OBJECTIVES: The aim of this study is to investigate the association of the 5-HTTLPR and rs25531 polymorphisms, using bi- and triallelic approach, with dietary intake and anthropometric parameters in children followed until 8 years old. METHODS: The sample were 303 children who were recruited at birth and examined at 1, 3 to 4 and 7 to 8 years old. The polymorphisms were analyzed by polymerase-chain-reaction-based methods. RESULTS: In the biallelic approach, children with the S/S genotype presented a higher body mass index Z-score in the three developmental stages and higher sum of skinfolds at 3 to 4 and 7 to 8 years old than carriers of the L allele. In the triallelic approach, S/S, Lg/S plus Lg/Lg genotypes were associated with higher energy intake daily at 1 year old and with waist circumference at 3 to 4 years old. CONCLUSIONS: In the biallelic approach, the 5-HTTLPR polymorphism is associated with food intake, body mass index Z-score and sum of skinfolds in children, reinforcing the role of the serotonin transporter in childhood obesity. Our data indicate that the biallelic approach is more sensible than the triallelic approach for detected associations with food intake and nutritional status in childhood. Identifying susceptibility genes in early life could provide the foundations for interventions in lifestyle to prevent children to become obese adults.

Asunto(s)

Ingestión de Alimentos/genética , Estado Nutricional/genética , Polimorfismo de Nucleótido Simple , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Alelos , Índice de Masa Corporal , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino

RESUMEN

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.

Asunto(s)

Trastorno por Déficit de Atención con Hiperactividad/genética , Glutamato Descarboxilasa/genética , Adolescente , Alelos , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Niño , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Glutamato Descarboxilasa/metabolismo , Haplotipos , Humanos , Hipercinesia/genética , Hipercinesia/psicología , Conducta Impulsiva , Masculino , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Índice de Severidad de la Enfermedad

RESUMEN

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.

Asunto(s)

Envejecimiento , Trastorno por Déficit de Atención con Hiperactividad/genética , Óxido Nítrico Sintasa de Tipo I/genética , Polimorfismo Genético/genética , Proteína 25 Asociada a Sinaptosomas/genética , Adolescente , Adulto , Niño , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Estadísticas no Paramétricas , Adulto Joven

RESUMEN

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.

Asunto(s)

Trastorno por Déficit de Atención con Hiperactividad/genética , Trastornos de la Memoria/genética , Memoria a Corto Plazo/fisiología , Proteínas Asociadas a Microtúbulos/genética , Óxido Nítrico Sintasa de Tipo I/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Factores de Edad , Análisis de Varianza , Trastorno por Déficit de Atención con Hiperactividad/complicaciones , Niño , Preescolar , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Pruebas de Inteligencia , Masculino , Trastornos de la Memoria/etiología , Pruebas Neuropsicológicas , Escalas de Valoración Psiquiátrica

RESUMEN

Variants of dopamine system genes such as the DRD4 and the SLC6A3 genes may be involved in food intake regulation because the dopaminergic system influences food reward. We investigated an association of polymorphisms in the DRD4 (exon 3 VNTR) and SLC6A3 (3'UTR VNTR, rs2550948, rs2652511 and rs1048953) genes with food intake and nutritional status in children. This prospective cohort study recruited 359 children at birth. Dietary data and nutritional status were collected at 1 year, 3-4 years, and 7-8 years of age. The polymorphisms were analyzed using polymerase chain reaction based techniques. Food intake and nutritional status were compared among the different SNP genotypes. In the first year of life, DRD4.7R- children showed higher BMI Z-scores (P=.019) than the DRD4.7R+ cohort. At 3-4 years old, DRD4.7R- and SLC6A3.10R/10R children showed a higher intake of palatable foods (P=.024) and a higher waist circumference (P=.017). The rs1048953 SLC6A3 polymorphism was associated with average daily energy intake (P=.003) at 3-4 years and with a waist-to-height ratio of children at 7-8 years (P=.041). Carriers of high dopamine activity alleles of the VNTRs studied in DRD4 and SLC6A3 genes and carriers of T/T genotype of the variant rs1048953 SLC6A3 can present an increased risk for obesity related to overeating because high dopamine activity can increase the perceived incentive value of food reward.

Asunto(s)

Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Ingestión de Alimentos , Estado Nutricional , Polimorfismo Genético , Receptores de Dopamina D4/genética , Regiones no Traducidas 3' , Alelos , Niño , Preescolar , Dopamina/química , Exones , Frecuencia de los Genes , Genotipo , Humanos , Lactante , Estudios Prospectivos , Relación Cintura-Estatura

RESUMEN

BACKGROUND: Serotonin plays a critical role in the regulation of food intake. The solute carrier family 6 member 14 (SLC6A14) and serotonin receptor 2C (5-HTR2C) genes are involved in the bioavailability and action of this neurotransmitter. OBJECTIVE: Evaluation of the association of six polymorphisms in these genes with food intake and nutritional status in children followed to 7-8years of age. DESIGN: Blood samples and the biodemographic data of 344 children were collected at three development stages, in a cross-sectional study undertaken with the cohort from a randomized trial. Polymorphisms were analyzed using polymerase chain reaction-based techniques. RESULTS: At 7 to 8years of age, carriers of the A alleles for both the SLC6A14 rs2312054 and SLC6A14 rs12391221 polymorphisms showed higher food intake, except for the sugar-dense food (SDF) intake parameter, than T/T and C/C homozygotes, respectively. Boy carriers of the C allele of rs2071877 had a higher sum of triceps and subscapular folds than T allele carriers at 7 to 8years old. For 5-HTR2C gene variants, A allele carriers (rs3813928) and T allele carriers (rs3813929) had higher food intake at 3 to 4years old than G/G and C/C homozygotes, respectively, except for SDF. At this age, the intake of energy-dense foods was higher in carriers of the T allele (rs3813929) than in C/C homozygotes. CONCLUSION: This study provides evidence that genetic variants of these proteins might be involved in the determination of food intake and nutritional status in children.

Asunto(s)

Sistemas de Transporte de Aminoácidos Neutros/genética , Ingestión de Alimentos/genética , Estado Nutricional/genética , Polimorfismo de Nucleótido Simple , Receptor de Serotonina 5-HT2C/genética , Alelos , Sistemas de Transporte de Aminoácidos , Niño , Preescolar , Estudios Transversales , Femenino , Expresión Génica , Frecuencia de los Genes , Genotipo , Heterocigoto , Homocigoto , Humanos , Lactante , Masculino , Ensayos Clínicos Controlados Aleatorios como Asunto

Asunto(s)

Trastorno por Déficit de Atención con Hiperactividad/genética , Receptores de Glutamato Metabotrópico/genética , Adolescente , Humanos

RESUMEN

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.

Asunto(s)

Alelos , Citocromo P-450 CYP2D6/genética , Duplicación de Gen , Frecuencia de los Genes , Fenotipo , Polimorfismo de Nucleótido Simple , Población Negra , Brasil , Femenino , Humanos , Masculino , Población Blanca

RESUMEN

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder with a strong genetic component. The glutamate metabotropic receptor genes (GRMs) have been considered potential candidates for ADHD susceptibility. The aim of the present study was to investigate if copy number variants (CNVs) in GRM1, GRM5, and GRM8 genes are overrepresented in ADHD subjects. A total of 1038 individuals with ADHD and 1057 subjects without this disorder were investigated. No significant difference in the total number of CNVs was found comparing the entire ADHD sample and the population sample without ADHD (P = 0.326, OR = 1.112, 95% CI = 0.762-1.624). The presence of CNVs was associated with lower intelligence quotient (IQ) scores in ADHD samples (P = 0.026, OR = 1.824, 95% CI = 1.066-3.121) but not in the sample of individuals without ADHD. CNVs in GRM5 were associated with presence of anxiety disorders in ADHD cases (P = 0.002, OR = 3.915, 95% CI = 1.631-9.402), but not in individuals without ADHD. Taken together, our results suggest a role for glutamate in ADHD as CNVs in the glutamatergic genes investigated herein were associated with cognitive and clinical characteristics of ADHD individuals.

Asunto(s)

Trastorno por Déficit de Atención con Hiperactividad/genética , Variaciones en el Número de Copia de ADN/genética , Receptores de Glutamato Metabotrópico/genética , Adulto , Ansiedad/genética , Estudios de Casos y Controles , Niño , Femenino , Humanos , Masculino

RESUMEN

The dopamine receptor D4 (DRD4) is one of the most studied candidate genes for Attention-Deficit/Hyperactivity Disorder (ADHD). An excess of rare variants and non-synonymous mutations in the VNTR region of 7R allele in ADHD subjects was observed in previous studies with clinical samples. We hypothesize that genetic heterogeneity in the VNTR is an important factor in the pathophysiology of ADHD. The subjects included in the present study are members of the 1993 Pelotas Birth Cohort Study (N=5,249). We conducted an association study with the 4,101 subjects who had DNA samples collected. The hyperactivity-inattention scores were assessed through the parent version of the Strengths and Difficulties Questionnaire at 11 and 15 years of age. The contribution of allele's length and rare variants to high hyperactivity/inattention scores predisposition was evaluated by multivariate logistic regression. No effect of allele length was observed on high scores of hyperactivity-inattention. By contrast, when resequencing/haplotyping was conducted in a subsample, all 7R rare variants as well as non-synonymous 7R rare variants were associated with high hyperactivity/inattention scores (OR=2.561; P=0.024 and OR=3.216; P=0.008 respectively). A trend for association was observed with 4R rare variants. New coding mutations covered 10 novel motifs and many of them are previously unreported deletions leading to different stop codons. Our findings suggest a contribution of DRD4 7R rare variants to high hyperactivity-inattention scores in a population-based sample from a large birth cohort. These findings provide further evidence for an effect of DRD4 7R rare variants and allelic heterogeneity in ADHD genetic susceptibility.

Asunto(s)

Trastorno por Déficit de Atención con Hiperactividad/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética , Receptores de Dopamina D4/genética , Adolescente , Trastorno por Déficit de Atención con Hiperactividad/patología , Secuencia de Bases , Brasil , Niño , Estudios de Cohortes , Estudios de Asociación Genética , Haplotipos/genética , Humanos , Modelos Logísticos , Repeticiones de Minisatélite/genética , Datos de Secuencia Molecular , Oportunidad Relativa , Análisis de Secuencia de ADN , Encuestas y Cuestionarios

RESUMEN

BACKGROUND: The study of gene-environment interactions (G × E) is one of the most promising strategies to uncover the origins of mental disorders. Replication of initial findings, however, is essential because there is a strong possibility of publication bias in the literature. In addition, there is a scarcity of research on the topic originated from low- and middle-income countries (LMIC). The aim of this study was to replicate G × E hypotheses for externalizing problems among adolescents in a middle-income country. METHODS: As part of the Pelotas 1993 Birth Cohort Study, 5,249 children were enrolled at birth and followed up to the age of 15 years, with an 85.7% retention rate. We sought an interaction between the homozygosity of the 10-repeat allele at the dopamine transporter (DAT1) gene and prenatal maternal smoking in the development of hyperactivity problems during adolescence assessed by the Strengths and Difficulties Questionnaire. We also tested for an interaction between the uVNTR polymorphism at the monoamine oxidase A (MAOA) and the experience of childhood maltreatment in the occurrence of conduct problems among adolescent boys. RESULTS: Although there was a clear association between prenatal maternal smoking and hyperactivity scores in adolescence (p < 0.001), no main genetic or interaction effects for the DAT1 gene were detected. Similarly, childhood maltreatment showed to be associated with conduct problems among boys (p < 0.001), with no observable main genetic or interaction effects for the MAOA gene. CONCLUSIONS: In the largest mental health G × E study performed in a LMIC to date, we did not replicate previous positive findings from the literature. Despite the presence of main environmental effects, there was no evidence of effect modification by genotype status. Additional replication efforts to measure G × E are needed to better understand the origins of mental health and illness, especially in LMIC.

Asunto(s)

Déficit de la Atención y Trastornos de Conducta Disruptiva/etiología , Maltrato a los Niños/psicología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Interacción Gen-Ambiente , Monoaminooxidasa/genética , Fumar/genética , Adolescente , Brasil/epidemiología , Niño , Estudios de Cohortes , Femenino , Homocigoto , Humanos , Estudios Longitudinales , Masculino , Conducta Materna , Embarazo , Fumar/epidemiología

RESUMEN

COMT Val(158)Met polymorphism has been associated with both symptoms of attention-deficit/hyperactivity disorder (ADHD) and disruptive behavior disorders (DBD): that is, oppositional defiant disorder (ODD) and conduct disorder (CD) often comorbid with ADHD. The aim of this study was to test the association between COMT Val(158)Met polymorphism and the presence of DBD in children with ADHD (n = 516). Homozygous Val/Val children showed a higher prevalence of ADHD comorbid with DBD (χ(2) = 5.762; p = 0.016; OR = 1.58; CI(95%) = 1.07-2.35). Our findings replicate previous results and suggest a role for COMT in the etiology of DBD in children and adolescents with ADHD.

Asunto(s)

Trastorno por Déficit de Atención con Hiperactividad/genética , Déficit de la Atención y Trastornos de Conducta Disruptiva/genética , Catecol O-Metiltransferasa/genética , Adolescente , Alelos , Sustitución de Aminoácidos , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/psicología , Déficit de la Atención y Trastornos de Conducta Disruptiva/epidemiología , Déficit de la Atención y Trastornos de Conducta Disruptiva/psicología , Brasil/epidemiología , Niño , Comorbilidad , Trastorno de la Conducta/genética , Trastorno de la Conducta/psicología , ADN/genética , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Pruebas Neuropsicológicas , Polimorfismo Genético , Valina/genética

RESUMEN

The frequency distribution of SNPs and haplotypes in the ABCB1, SLCO1B1 and SLCO1B3 genes varies largely among continental populations. This variation can lead to biases in pharmacogenetic studies conducted in admixed populations such as those from Brazil and other Latin American countries. The aim of this study was to evaluate the influence of self-reported colour, geographical origin and genomic ancestry on distributions of the ABCB1, SLCO1B1 and SLCO1B3 polymorphisms and derived haplotypes in admixed Brazilian populations. A total of 1039 healthy adults from the north, north-east, south-east and south of Brazil were recruited for this investigation. The c.388A>G (rs2306283), c.463C>A (rs11045819) and c.521T>C (rs4149056) SNPs in the SLCO1B1 gene and c.334T>G (rs4149117) and c.699G>A (rs7311358) SNPs in the SLCO1B3 gene were determined by Taqman 5'-nuclease assays. The ABCB1 c.1236C>T (rs1128503), c.2677G>T/A (rs2032582) and c.3435C>T (rs1045642) polymorphisms were genotyped using a previously described single-base extension/termination method. The results showed that genotype and haplotype distributions are highly variable among populations of the same self-reported colour and geographical region. However, genomic ancestry showed that these associations are better explained by a continuous variable. The influence of ancestry on the distribution of alleles and haplotype frequencies was more evident in variants with large differences in allele frequencies between European and African populations. Design and interpretation of pharmacogenetic studies using these transporter genes should include genomic controls to avoid spurious conclusions based on improper matching of study cohorts from Brazilian populations and other highly admixed populations.

Asunto(s)

Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Genética de Población , Transportadores de Anión Orgánico Sodio-Independiente/genética , Transportadores de Anión Orgánico/genética , Polimorfismo de Nucleótido Simple , Grupos Raciales/genética , Subfamilia B de Transportador de Casetes de Unión a ATP , Brasil , Estudios de Cohortes , Frecuencia de los Genes , Haplotipos , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado , Terapia Molecular Dirigida , Farmacogenética , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos

RESUMEN

BACKGROUND: The catechol-O-methyltransferase enzyme plays a key role in the function of prefrontal cortex, accounting for most of the degradation of dopamine. Previous studies have documented the improvement of oppositional symptoms in attention-deficit/hyperactivity disorder (ADHD) patients with methylphenidate (MPH) treatment. However, the effect of the COMT gene in the response to MPH on oppositional symptoms has not been investigated. METHODS: A total of 251 children with ADHD fulfilled inclusion criteria to participate in the study. Dosages of short-acting MPH were augmented until no further clinical improvement was detected or until there were significant adverse events (MPH dose always > .3 mg/kg/day). The outcome measure was the parent-rated oppositional subscale of the Swanson, Nolan and Pelham Scale-Version IV (SNAP-IV). The scale was applied by child psychiatrists blinded to genotype at baseline and in the first and third months. The COMT valine158methionine polymorphism was genotyped by polymerase chain reaction based methods. RESULTS: We detected significant improvement in SNAP-IV oppositional scores from baseline to the first and three months of treatment [n = 112; F(2,231) = 5.35, p = .005]. A significant effect of the presence of methionine allele in oppositional defiant disorder scores during treatment [F(1,148) = 5.02, p = .027] and a significant interaction between the methionine allele and treatment over time for the SNAP-IV oppositional scores during this period of treatment [F(2,229) = 6.40, p = .002] were both observed. CONCLUSIONS: These results suggest an effect of the COMT genotype on the trajectory of oppositional defiant disorder symptoms improvement with MPH treatment in boys with ADHD.

Asunto(s)

Trastorno por Déficit de Atención con Hiperactividad/genética , Catecol O-Metiltransferasa/genética , Estimulantes del Sistema Nervioso Central/uso terapéutico , Metilfenidato/uso terapéutico , Polimorfismo de Nucleótido Simple , Adolescente , Conducta del Adolescente/efectos de los fármacos , Conducta del Adolescente/fisiología , Alelos , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno por Déficit de Atención con Hiperactividad/enzimología , Niño , Conducta Infantil/efectos de los fármacos , Conducta Infantil/fisiología , Preescolar , Frecuencia de los Genes , Genotipo , Humanos , Masculino

RESUMEN

PURPOSE: Attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) are highly comorbid and may share a genetic vulnerability. Methylphenidate (MPH), a dopamine transporter (DAT) blocker, is an effective drug for most ADHD patients. Although dopamine D4 receptor (DRD4) and dopamine transporter (DAT1) genes have a role in both disorders, little is known about how these genes influence brain response to MPH in individuals with ADHD/SUDs. The goal of this study was to evaluate whether ADHD risk alleles at DRD4 and DAT1 genes could predict the change in striatal DAT occupancy after treatment with MPH in adolescents with ADHD/SUDs. METHODS: Seventeen adolescents with ADHD/SUDs underwent a SPECT scan with [Tc(99m) ]TRODAT-1 at baseline and after three weeks on MPH. Caudate and putamen DAT binding potential was calculated. Comparisons on DAT changes were made according to the subjects' genotype. RESULTS: The combination of both DRD4 7-repeat allele (7R) and homozygosity for the DAT1 10-repeat allele (10/10) was significantly associated with a reduced DAT change after MPH treatment in right and left caudate and putamen, even adjusting the results for potential confounders (P ≤ 0.02; R² from 0.50 to 0.56). CONCLUSIONS: In patients with ADHD/SUDs, combined DRD4 7R and DAT1 10/10 could index MPH reduced DAT occupancy. This might be important for clinical trials, in terms of better understanding individual variability in treatment response.

Asunto(s)

Trastorno por Déficit de Atención con Hiperactividad , Mapeo Encefálico , Inhibidores de Captación de Dopamina/uso terapéutico , Metilfenidato/uso terapéutico , Trastornos Relacionados con Sustancias , Adolescente , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico por imagen , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/genética , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/patología , Comorbilidad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Inhibidores de Captación de Dopamina/farmacología , Esquema de Medicación , Sistemas de Liberación de Medicamentos , Frecuencia de los Genes , Genotipo , Humanos , Modelos Lineales , Masculino , Metilfenidato/farmacología , Compuestos de Organotecnecio/farmacocinética , Radiofármacos/farmacocinética , Receptores de Dopamina D4/genética , Trastornos Relacionados con Sustancias/diagnóstico por imagen , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Trastornos Relacionados con Sustancias/epidemiología , Trastornos Relacionados con Sustancias/genética , Tomografía Computarizada de Emisión de Fotón Único/métodos , Tropanos/farmacocinética , Adulto Joven

RESUMEN

Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric condition that affects approximately 5.3% of children worldwide. This disorder is defined by a combination of symptoms of inattention and hyperactivity/impulsivity. Diagnosis is based on impairment in these two domains determining several problems in personal and academic life. Although it is known that genetic and environmental factors are important in ADHD etiology, how these factors influence the brain and consequently behavior is still under debate. There seems to be a consensus in the literature that a fronto-subcortical dysfunction is responsible, at least in part, for the ADHD spectrum. Considering that these brain regions are rich in dopamine (DA), the DA hypothesis has an important role to understand ADHD pathophysiology. The main goal of the present review is to show evidence from different areas that support the idea that dysregulation in the DA system underlies ADHD. We discuss here evidences from animal models, pharmacology, brain imaging and genetics studies.

Asunto(s)

Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Dopamina/metabolismo , Animales , Trastorno por Déficit de Atención con Hiperactividad/etiología , Encéfalo/metabolismo , Encéfalo/fisiopatología , Humanos