RESUMO
The subject of disabilities that include cognition and adaptability will never cease to be interesting and relevant. The genetic etiology has more weight every day. The relationship with other neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) is of clinical, diagnostic and therapeutic importance. The objective was to conduct a review of intellectual development disorder and its implication with ASD and ADHD. From Hippocrates to the present the disorders that affect learning, behavior and socialization skills have been the subject of studies and have varied, above all, in the denomination as an entity and its perception from the human and social point of view. The etiology of intellectual development disorders in most cases is an enigma and genetic advances are the cornerstone to elucidate the origin of this neurodevelopmental disorder, as well as its relationship with others such as ASD and ADHD. The disorder of intellectual development, the oldest one with respect to definition, study and approach, still presents mysteries above all of etiological origin. Its relationship with other neurodevelopmental disorders such as ASD and ADHD is evident by having common areas of involvement, which may be coincident diagnoses.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/genética , Deficiência Intelectual/genética , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/fisiopatologia , Cognição , Comorbidade , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/fisiopatologiaRESUMO
BACKGROUND: Twin studies using both clinical and population-based samples suggest that the frequent co-occurrence of attention deficit hyperactivity disorder (ADHD) and reading ability/disability (RD) is largely driven by shared genetic influences. While both disorders are associated with lower IQ, recent twin data suggest that the shared genetic variability between reading difficulties and ADHD inattention symptoms is largely independent from genetic influences contributing to general cognitive ability. The current study aimed to extend the previous findings that were based on rating scale measures in a population sample by examining the generalisability of the findings to a clinical population, and by measuring reading difficulties both with a rating scale and with an objective task. This study investigated the familial relationships between ADHD, reading difficulties and IQ in a sample of individuals diagnosed with ADHD combined type, their siblings and control sibling pairs. METHODS: Multivariate familial models were run on data from 1,789 individuals at ages 6-19. Reading difficulties were measured with both rating scale and an objective task. IQ was obtained using the Wechsler Intelligence Scales (WISC-III/WAIS-III). RESULTS: Significant phenotypic (.2-.4) and familial (.3-.5) correlations were observed among ADHD, reading difficulties and IQ. Yet, 53%-72% of the overlapping familial influences between ADHD and reading difficulties were not shared with IQ. CONCLUSIONS: Our finding that familial influences shared with general cognitive ability, although present, do not account for the majority of the overlapping familial influences on ADHD and reading difficulties extends previous findings from a population-based study to a clinically ascertained sample with combined type ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/complicações , Dislexia/complicações , Inteligência , Irmãos/psicologia , Adolescente , Testes de Aptidão , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Criança , Dislexia/psicologia , Feminino , Humanos , Masculino , Inquéritos e Questionários , Escalas de Wechsler , Adulto JovemRESUMO
BACKGROUND: Emotional lability (EL) is commonly seen in patients with attention-deficit/hyperactivity disorder (ADHD). The reasons for this association remain currently unknown. To address this question, we examined the relationship between ADHD and EL symptoms, and performance on a range of neuropsychological tasks to clarify whether EL symptoms are predicted by particular cognitive and/or motivational dysfunctions and whether these associations are mediated by the presence of ADHD symptoms. METHODS: A large multi-site sample of 424 carefully diagnosed ADHD cases and 564 unaffected siblings and controls aged 6-18 years performed a broad neuropsychological test battery, including a Go/No-Go Task, a warned four-choice Reaction Time task, the Maudsley Index of Childhood Delay Aversion and Digit span backwards. Neuropsychological variables were aggregated as indices of processing speed, response variability, executive functions, choice impulsivity and the influence of energetic and/or motivational factors. EL and ADHD symptoms were regressed on each neuropsychological variable in separate analyses controlling for age, gender and IQ, and, in subsequent regression analyses, for ADHD and EL symptoms respectively. RESULTS: Neuropsychological variables significantly predicted ADHD and EL symptoms with moderate-to-low regression coefficients. However, the association between neuropsychological parameters on EL disappeared entirely when the effect of ADHD symptoms was taken into account, revealing that the association between the neuropsychological performance measures and EL is completely mediated statistically by variations in ADHD symptoms. Conversely, neuropsychological effects on ADHD symptoms remained after EL symptom severity was taken into account. CONCLUSIONS: The neuropsychological parameters examined, herein, predict ADHD more strongly than EL. They cannot explain EL symptoms beyond what is already accounted for by ADHD symptom severity. The association between EL and ADHD cannot be explained by these cognitive or motivational deficits. Alternative mechanisms, including overlapping genetic influences (pleiotropic effects) and/or alternative neuropsychological processes need to be considered.
Assuntos
Transtornos de Deficit da Atenção e do Comportamento Disruptivo/fisiopatologia , Emoções/fisiologia , Desempenho Psicomotor/fisiologia , Adolescente , Criança , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Índice de Gravidade de Doença , IrmãosRESUMO
Attention deficit hyperactivity disorder (ADHD) is the most prevalent and frequent neurodevelopmental disorder in neuropediatrics, child psychiatry and child psychology consultations. The greater awareness of this condition, the information and, above all, the socio-cultural acceptance, has led to an earlier diagnosis, leading to more timely and effective treatment. Individualizing each case through systematic tools such as neuropsychological studies and their neuroanatomical and neurobiochemical correlation, related to ADHD, together with algorithms that analyze executive functions, is essential to indicate the optimal pharmacological treatment, together with the application of appropriate non-pharmacological therapies. Multimodal treatment, with cognitive behavioral intervention and pharmacological treatment, is the most effective therapeutic approach.
El trastorno por déficit de atención e hiperactividad (TDAH) es el trastorno del neurodesarrollo más prevalente y frecuente en las consultas de neuropediatría, psiquiatría y psicología infantiles. La mayor sensibilización ante esta condición, la información y sobre todo la aceptación socio cultural, ha provocado que se diagnostique más precozmente, implicando ello un tratamiento más oportuno y eficaz. El individualizar cada caso mediante herramientas sistemáticas como los estudios neuropsicológicos y su correlación neuroanatómica y neurobioquímica, relacionados con el TDAH, junto con los algoritmos que analizan las funciones ejecutivas, es primordial para indicar el tratamiento farmacológico óptimo, unido a la aplicación de las terapias no farmacológicas apropiadas. El tratamiento multimodal, con intervención cognitivo conductual y tratamiento farmacológico, es el enfoque terapéutico más efectivo.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/terapia , Criança , Função Executiva , Humanos , Resultado do TratamentoRESUMO
Intelligence is a highly heritable trait for which it has proven difficult to identify the actual genes. In the past decade, five whole-genome linkage scans have suggested genomic regions important to human intelligence; however, so far none of the responsible genes or variants in those regions have been identified. Apart from these regions, a handful of candidate genes have been identified, although most of these are in need of replication. The recent growth in publicly available data sets that contain both whole genome association data and a wealth of phenotypic data, serves as an excellent resource for fine mapping and candidate gene replication. We used the publicly available data of 947 families participating in the International Multi-Centre ADHD Genetics (IMAGE) study to conduct an in silico fine mapping study of previously associated genomic locations, and to attempt replication of previously reported candidate genes for intelligence. Although this sample was ascertained for attention deficit/hyperactivity disorder (ADHD), intelligence quotient (IQ) scores were distributed normally. We tested 667 single nucleotide polymorphisms (SNPs) within 15 previously reported candidate genes for intelligence and 29451 SNPs in five genomic loci previously identified through whole genome linkage and association analyses. Significant SNPs were tested in four independent samples (4,357 subjects), one ascertained for ADHD, and three population-based samples. Associations between intelligence and SNPs in the ATXN1 and TRIM31 genes and in three genomic locations showed replicated association, but only in the samples ascertained for ADHD, suggesting that these genetic variants become particularly relevant to IQ on the background of a psychiatric disorder.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Inteligência/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Ubiquitina-Proteína Ligases/genética , Ataxina-1 , Ataxinas , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Estudos de Coortes , Humanos , Metanálise como Assunto , Núcleo Familiar , Fenótipo , Polimorfismo de Nucleotídeo Único , Proteínas com Motivo Tripartido , População Branca/genética , População Branca/estatística & dados numéricosRESUMO
BACKGROUND: The goal of this study was to investigate the occurrence, severity and clinical correlates of emotional lability (EL) in children with attention deficit/hyperactivity disorder (ADHD), and to examine factors contributing to EL and familiality of EL in youth with ADHD. METHODS: One thousand, one hundred and eighty-six children with ADHD combined type and 1827 siblings (aged 6-18 years) were assessed for symptoms of EL, ADHD, associated psychopathology and comorbid psychiatric disorders with a structured diagnostic interview (PACS) as well as parent and teacher ratings of psychopathology (SDQ; CPRS-R:L; CTRS-R:L). Analyses of variance, regression analyses, chi(2)-tests or loglinear models were applied. RESULTS: Mean age and gender-standardized ratings of EL in children with ADHD were >1.5 SD above the mean in normative samples. Severe EL (>75th percentile) was associated with more severe ADHD core symptoms, primarily hyperactive-impulsive symptoms, and more comorbid oppositional defiant, affective and substance use disorders. Age, hyperactive-impulsive, oppositional, and emotional symptoms accounted for 30% of EL variance; hyperactive-impulsive symptoms did not account for EL variance when coexisting oppositional and emotional problems were taken into account, but oppositional symptoms explained 12% of EL variance specifically. Severity of EL in probands increased the severity of EL in siblings, but not the prevalence rates of ADHD or ODD. EL and ADHD does not co-segregate within families. CONCLUSION: EL is a frequent clinical problem in children with ADHD. It is associated with increased severity of ADHD core symptoms, particularly hyperactivity-impulsivity, and more symptoms of comorbid psychopathology, primarily symptoms of oppositional defiant disorder (ODD), but also affective symptoms, and substance abuse. EL in ADHD seems to be more closely related to ODD than to ADHD core symptoms, and is only partly explainable by the severity of ADHD core symptoms and associated psychopathology. Although EL symptoms are transmitted within families, EL in children with ADHD does not increase the risk of ADHD and ODD in their siblings.
Assuntos
Sintomas Afetivos/diagnóstico , Sintomas Afetivos/genética , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Adolescente , Sintomas Afetivos/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/diagnóstico , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/genética , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/psicologia , Criança , Comorbidade , Transtorno da Conduta/diagnóstico , Transtorno da Conduta/genética , Transtorno da Conduta/psicologia , Estudos Transversais , Feminino , Humanos , Inibição Psicológica , Controle Interno-Externo , Modelos Lineares , Masculino , Modelos Psicológicos , Determinação da Personalidade/estatística & dados numéricos , Fenótipo , Psicometria , Psicopatologia , Ajustamento Social , Estatística como Assunto , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/psicologiaRESUMO
Theta-Beta (T / B) ratio of the quantified electroencephalogram (EEGQ) in patients with attention deficit hyperactivity disorder (ADHD) constitutes a characteristic EEG variable of the primary disorder with an overall accuracy of 89%. The objective of this study was to measure the T/B ratio in a sample of patients with ADHD and the effects of the treatment with psychostimulants and non-psychostimulants on the T/B ratio. The sample consisted of 85 children between 6 and 18 years (68 males and 17 females) with the diagnosis of the inattentive and combined subtype of ADHD, according to the criteria of the DSM-V. An EEGQ was performed with measurement of the T/B ratio before and after 6 months of treatment with psychostimulant and non-psychostimulant drugs. Both groups were compared using the Wilcoxon signed range test for related samples. The results showed that 86% of the cases had a T/B ratio above the normal values for the age of them. The reduction in the T/B ratio was statistically significant in the group of patients treated with psychostimulants. The reduction of non-psychostimulants was not significant. In conclusion, we confirmed the high T/B ratio in patients with ADHD. Psychostimulant drugs decrease the elevated T/B ratio in patients with ADHD after 6 months of treatment.
El cociente Theta-Beta (T/B) del electroencefalograma cuantificado (EEGQ) de los pacientes con trastorno por déficit de atención e hiperactividad (TDAH) constituye una variable del EEG característica del trastorno primario con una precisión global del 89%. El objetivo de este estudio es medir el cociente T/B de una población de con TDAH y los efectos del tratamiento farmacológico con psicoestimulantes y no psicoestimulantes sobre el cociente T/B. La muestra estaba formada por 85 sujetos de entre 6 y los 18 años (68 niños y 17 niñas) con el diagnóstico de TDAH de subtipo inatento y combinado, según los criterios del DSM-V. Se les realizó un EEGQ con medición del cociente T/B antes y después de 6 meses de tratamiento con fármacos psicoestimulantes y no psicoestimulantes. Se compararon ambos grupos mediante la prueba de rangos con signo de Wilcoxon para muestras relacionadas. En el 86% de los casos el cociente T/B fue elevado respecto de los valores normales para la edad. La reducción en el cociente T/B fue significativa en el grupo tratado con psicoestimulantes aunque la reducción con los no psicoestimulantes no fue significativa. En conclusión, se confirma la elevación del cociente T/B en los pacientes con TDAH. Los fármacos psicoestimulantes disminuyen de forma significativa el cociente T/B elevado en los pacientes con TDAH tras 6 meses de tratamiento.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Ritmo beta/fisiologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Eletroencefalografia/métodos , Ritmo Teta/fisiologia , Adolescente , Fatores Etários , Criança , Feminino , Humanos , Masculino , Valores de Referência , Estatísticas não Paramétricas , Resultado do TratamentoRESUMO
Children with attention deficit/hyperactivity disorder (ADHD) choose smaller sooner (SS) over larger later (LL) rewards more than controls. Here we assess the contributions of impulsive drive for immediate rewards (IDIR) and delay aversion (DAv) to this pattern. We also explore the characteristics of, and the degree of familiality in, ADHD SS responders. We had 360 ADHD probands; 349 siblings and 112 controls (aged between 6 to 17 years) chose between SS (1 point after 2 s) and LL reward (2 points after 30 s) outcomes on the Maudsley Index of Delay Aversion (Kuntsi, Oosterlaan, & Stevenson, 2001): Under one condition SS choice led to less overall trial delay under another it did not. ADHD participants chose SS more than controls under both conditions. This effect was larger when SS choice reduced trial delay. ADHD SS responders were younger, had lower IQ, more conduct disorder and had siblings who were more likely to be SS responders themselves. The results support a dual component model in which both IDIR and DAv contribute to SS choice in ADHD. SS choice may be a marker of an ADHD motivational subtype.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Comportamento de Escolha , Comportamento Impulsivo/psicologia , Desempenho Psicomotor , Tempo de Reação , Recompensa , Adolescente , Análise de Variância , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Estudos de Casos e Controles , Criança , Feminino , Humanos , Modelos Logísticos , Masculino , Testes Neuropsicológicos/estatística & dados numéricos , Irmãos , Fatores de TempoRESUMO
It is hypothesised that autism symptoms are present in Attention-Deficit/Hyperactivity Disorder (ADHD), are familial and index subtypes of ADHD. Autism symptoms were compared in 821 ADHD probands, 1050 siblings and 149 controls. Shared familiality of autism symptoms and ADHD was calculated using DeFries-Fulker analysis. Autism symptoms were higher in probands than siblings or controls, and higher in male siblings than male controls. Autism symptoms were familial, partly shared with familiality of ADHD in males. Latent class analysis using SCQ-score yielded five classes; Class 1(31%) had few autism symptoms and low comorbidity; Classes 2-4 were intermediate; Class 5(7%) had high autism symptoms and comorbidity. Thus autism symptoms in ADHD represent a familial trait associated with increased neurodevelopmental and oppositional/conduct disorders.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno Autístico/epidemiologia , Atividade Motora , Irmãos , Transtorno do Deficit de Atenção com Hiperatividade/classificação , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno Autístico/diagnóstico , Transtorno Autístico/fisiopatologia , Criança , Pré-Escolar , Comorbidade , Transtorno da Conduta/epidemiologia , Medo/psicologia , Feminino , Humanos , Transtornos do Desenvolvimento da Linguagem/epidemiologia , Masculino , Fenótipo , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Psicometria/métodos , Índice de Gravidade de Doença , Distribuição por Sexo , Irmãos/psicologia , Inquéritos e QuestionáriosRESUMO
The development and establishment of the normal sleep patterns are very important processes in the final anatomical and physiological architecture of the central nervous system. The relationship between sleep disturbances during childhood with neurodevelopmental disorders is complex and potentially synergistic. Sleep patterns are present since the fetal period but their structure and physiology is modified according with the maturation of the central nervous system. Sleep disorders and their relationship with attention deficit hyperactivity disorders(ADHD), autism spectrum disorders(ASD) and other neurodevelopmental disorders (TDN) are not well understood yet, but significant progresses have been made in understanding associations and potential etiological correlations. We reviewed sleep disturbances in NDT, in ADHD and in ASD. A greater understanding of the pleiotropic functions of the genes involved in sleepwake cycle disorders and deviations from neurological developme nt could lead to new diagnostic and therapeut ic strategies in an early stage in order to improve the quality of life of the patient, relatives and caregivers.
El sueño es uno de los actos fisiológicos más importantes para la estructuración funcional y anatómica de áreas del sistema nervioso central. Las alteraciones del sueño durante la infancia y su relación con trastornos del neurodesarrollo es compleja y sumam ente interesante, donde destaca la multiplicidad de causas de estos trastornos. Bajo esta premisa se realiza una revisión sobre las alteraciones del sueño en los trastornos del neurodesarrollo (TND), por déficit de atención e hiperactividad (TDAH) y del espectro autista (TEA). El sueño está presente desde la etapa fetal y va modificando su expresión en sintonía con la madurez del sistema nervioso central. Los trastornos del sueño y su relación con TDAH, TEA y otros TND son complejos, pero existen avances sobre la etiología de los mismos. Una mayor compresión de las funciones pleiotrópicas de los genes implicados en los trastornos del ciclo vigilia-sueño y en las desviaciones del desarrollo neurológico podría conducir a nuevas estrategias diagnósticas y terapéuticas de manera precoz con el fin de mejorar la calidad de vida del paciente, familiares y cuidadores.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Espectro Autista/complicações , Transtornos do Sono-Vigília/complicações , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/genética , Pré-Escolar , Ritmo Circadiano , Humanos , Transtornos do Sono-Vigília/diagnóstico , Transtornos do Sono-Vigília/genéticaRESUMO
Studies of gene x environment (G x E) interaction in ADHD have previously focused on known risk genes for ADHD and environmentally mediated biological risk. Here we use G x E analysis in the context of a genome-wide association scan to identify novel genes whose effects on ADHD symptoms and comorbid conduct disorder are moderated by high maternal expressed emotion (EE). SNPs (600,000) were genotyped in 958 ADHD proband-parent trios. After applying data cleaning procedures we examined 429,981 autosomal SNPs in 909 family trios. ADHD symptom severity and comorbid conduct disorder was measured using the Parental Account of Childhood Symptoms interview. Maternal criticism and warmth (i.e., EE) were coded by independent observers on comments made during the interview. No G x E interactions reached genome-wide significance. Nominal effects were found both with and without genetic main effects. For those with genetic main effects 36 uncorrected interaction P-values were <10(-5) implicating both novel genes as well as some previously supported candidates. These were found equally often for all of the interactions being investigated. The observed interactions in SLC1A1 and NRG3 SNPs represent reasonable candidate genes for further investigation given their previous association with several psychiatric illnesses. We find evidence for the role of EE in moderating the effects of genes on ADHD severity and comorbid conduct disorder, implicating both novel and established candidates. These findings need replicating in larger independent samples.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Emoções Manifestas , Estudo de Associação Genômica Ampla , Pais/psicologia , Adolescente , Alelos , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Criança , Pré-Escolar , Transportador 3 de Aminoácido Excitatório/genética , Feminino , Frequência do Gene , Marcadores Genéticos , Genoma Humano , Humanos , Entrevistas como Assunto , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Modelos Genéticos , Neurregulinas , Relações Pais-Filho , Polimorfismo de Nucleotídeo Único , Probabilidade , Locos de Características QuantitativasRESUMO
There are conflicting reports suggesting that the parental origin of transmitted risk alleles may play a role in the etiology of attention deficit/hyperactivity disorder (ADHD). A recent report by Hawi and colleagues observed a generalized paternal over-transmission of alleles associated with ADHD. This was not replicated in more recent studies. Using data from a large multicenter study we examined the overall and gene-specific parent of origin effect in 554 independent SNPs across 47 genes. Transmission disequilibrium and explicit parent of origin test were performed using PLINK. Overall parent of origin effect was tested by Chi-square. There was no overall parent of origin effect in the IMAGE sample (chi(1)(2) = 1.82, P = 0.117). Five markers in three genes, DDC, TPH2, and SLC6A2 showed nominal association (P < 0.01) with ADHD combined subtype when restricted to maternal or paternal transmission only. Following the initial report by Hawi and co-workers three studies, including this one, found no evidence to support an overall parent of origin effect for markers associated with ADHD. We cannot however, exclude gene-specific parent of origin effect in the etiology ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Interpretação Estatística de Dados , Predisposição Genética para Doença , Pais , Alelos , Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Distribuição de Qui-Quadrado , Família , Marcadores Genéticos , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Previous studies have found heterogeneous association between DAT1-3'-UTR-VNTR and attention deficit hyperactivity disorder (ADHD). Various proportions of conduct disorder (CD) comorbidity in their ADHD samples may partially explain the observational discrepancies. Evidence for this comes from family and twin studies which found ADHD probands with CD (ADHD + CD) are genetically different from those without CD (ADHD - CD). Genotypes of 20 DAT1 markers were analyzed in 576 trios, consisting of 141 ADHD + CD and 435 ADHD - CD. In addition to the classical TDT test, a specific genetic heterogeneity test was performed to identify variants that have different transmission patterns in the two phenotypic subgroups. After multiple-test correction, rs40184 and rs2652511 were significant in TDT tests. Further heterogeneity test found the two SNPs had a significant transmission pattern difference between ADHD + CD and ADHD - CD children, indicating that DAT1 has a significantly greater genetic influence on ADHD without CD. Although the result needs further replications, it does highlight the importance of selecting genetically homogeneous samples for molecular genetic analyses of ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno da Conduta , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Heterogeneidade Genética , Alelos , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Distribuição de Qui-Quadrado , Criança , Comorbidade , Transtorno da Conduta/epidemiologia , Transtorno da Conduta/genética , Europa (Continente)/epidemiologia , Feminino , Frequência do Gene , Marcadores Genéticos , Genótipo , Haplótipos , Humanos , Incidência , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Attention deficit hyperactivity disorder (ADHD) is a complex condition with environmental and genetic etiologies. Up to this point, research has identified genetic associations with candidate genes from known biological pathways. In order to identify novel ADHD susceptibility genes, 600,000 SNPs were genotyped in 958 ADHD proband-parent trios. After applying data cleaning procedures we examined 429,981 autosomal SNPs in 909 family trios. We generated six quantitative phenotypes from 18 ADHD symptoms to be used in genome-wide association analyses. With the PBAT screening algorithm, we identified 2 SNPs, rs6565113 and rs552655 that met the criteria for significance within a specified phenotype. These SNPs are located in intronic regions of genes CDH13 and GFOD1, respectively. CDH13 has been implicated previously in substance use disorders. We also evaluated the association of SNPs from a list of 37 ADHD candidate genes that was specified a priori. These findings, along with association P-values with a magnitude less than 10(-5), are discussed in this manuscript. Seventeen of these candidate genes had association P-values lower then 0.01: SLC6A1, SLC9A9, HES1, ADRB2, HTR1E, DDC, ADRA1A, DBH, DRD2, BDNF, TPH2, HTR2A, SLC6A2, PER1, CHRNA4, SNAP25, and COMT. Among the candidate genes, SLC9A9 had the strongest overall associations with 58 association test P-values lower than 0.01 and multiple association P-values at a magnitude of 10(-5) in this gene. In sum, these findings identify novel genetic associations at viable ADHD candidate genes and provide confirmatory evidence for associations at previous candidate genes. Replication of these results is necessary in order to confirm the proposed genetic variants for ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Algoritmos , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Caderinas/genética , Análise por Conglomerados , Feminino , Marcadores Genéticos , Genoma Humano , Genótipo , Haplótipos , Humanos , Íntrons , Masculino , Modelos Genéticos , Linhagem , Polimorfismo de Nucleotídeo Único , ProbabilidadeRESUMO
A time-to-onset analysis for family-based samples was performed on the genomewide association (GWAS) data for attention deficit hyperactivity disorder (ADHD) to determine if associations exist with the age at onset of ADHD. The initial dataset consisted of 958 parent-offspring trios that were genotyped on the Perlegen 600,000 SNP array. After data cleaning procedures, 429,981 autosomal SNPs and 930 parent-offspring trios were used found suitable for use and a family-based logrank analysis was performed using that age at first ADHD symptoms as the quantitative trait of interest. No SNP achieved genome-wide significance, and the lowest P-values had a magnitude of 10(-7). Several SNPs among a pre-specified list of candidate genes had nominal associations including SLC9A9, DRD1, ADRB2, SLC6A3, NFIL3, ADRB1, SYT1, HTR2A, ARRB2, and CHRNA4. Of these findings SLC9A9 stood out as a promising candidate, with nominally significant SNPs in six distinct regions of the gene.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Estudo de Associação Genômica Ampla , Adolescente , Idade de Início , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Criança , Pré-Escolar , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Genoma Humano , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único , Probabilidade , Locos de Características Quantitativas , Estudos Retrospectivos , Trocadores de Sódio-Hidrogênio/genéticaRESUMO
Attention-deficit/hyperactivity disorder (ADHD) is typically characterized by inattention, excessive motor activity, impulsivity, and distractibility. Individuals with ADHD have significant impairment in family and peer relations, academic functioning, and show high co-morbidity with a wide range of psychiatric disorders including oppositional defiant disorder (ODD), conduct disorder (CD), anxiety disorder, depression, substance abuse, and pervasive developmental disorder (PDD). Family studies suggest that ADHD + CD represents a specific subtype of the ADHD disorder with familial risk factors only partly overlapping with those of ADHD alone. We performed a hypothesis-free analysis of the GAIN-ADHD sample to identify markers and genes important in the development of conduct problems in a European cohort of individuals with ADHD. Using the Family-Based Association Test (FBAT) package we examined three measures of conduct problems in 1,043,963 autosomal markers. This study is part of a series of exploratory analyses to identify candidate genes that may be important in ADHD and ADHD-related traits, such as conduct problems. We did not find genome-wide statistical significance (P < 5 x 10(-7)) for any of the tested markers and the three conduct problem traits. Fifty-four markers reached strong GWA signals (P < 10(-5)). We discuss these findings in the context of putative candidate genes and the implications of these findings in the understanding of the etiology of ADHD + CD. We aimed to achieve insight into the genetic etiology of a trait using a hypothesis-free study design and were able to identify a number of biologically interesting markers and genes for follow-up studies.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno da Conduta , Genoma Humano , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Algoritmos , Transtorno da Personalidade Antissocial/genética , Transtorno da Personalidade Antissocial/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/complicações , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/genética , Criança , Transtornos do Comportamento Infantil/epidemiologia , Transtornos do Comportamento Infantil/genética , Transtornos do Comportamento Infantil/psicologia , Estudos de Coortes , Comorbidade , Transtorno da Conduta/epidemiologia , Transtorno da Conduta/genética , Transtorno da Conduta/psicologia , Europa (Continente)/epidemiologia , Marcadores Genéticos , Humanos , Desequilíbrio de Ligação , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Polimorfismo de Nucleotídeo Único , Escalas de Graduação PsiquiátricaRESUMO
Results of behavioral genetic and molecular genetic studies have converged to suggest that genes substantially contribute to the development of attention deficit/hyperactivity disorder (ADHD), a common disorder with an onset in childhood. Yet, despite numerous linkage and candidate gene studies, strongly consistent and replicable association has eluded detection. To search for ADHD susceptibility genes, we genotyped approximately 600,000 SNPs in 958 ADHD affected family trios. After cleaning the data, we analyzed 438,784 SNPs in 2,803 individuals comprising 909 complete trios using ADHD diagnosis as phenotype. We present the initial TDT findings as well as considerations for cleaning family-based TDT data. None of the SNP association tests achieved genome-wide significance, indicating that larger samples may be required to identify risk loci for ADHD. We additionally identify a systemic bias in family-based association, and suggest that variable missing genotype rates may be the source of this bias.