RESUMO
Attention-deficit/hyperactivity disorder (ADHD) co-occurs with many other psychiatric disorders and traits. In this review, we summarize and interpret the existing literature on the genetic architecture of these comorbidities based on hypothesis-generating approaches. Quantitative genetic studies indicate that genetic factors play a substantial role in the observed co-occurrence of ADHD with many different disorders and traits. Molecular genetic correlations derived from genome-wide association studies and results of studies based on polygenic risk scores confirm the general pattern but provide effect estimates that are smaller than those from twin studies. The identification of the specific genetic variants and biological pathways underlying co-occurrence using genome-wide approaches is still in its infancy. The first analyses of causal inference using genetic data support causal relationships between ADHD and comorbid disorders, although bidirectional effects identified in some instances point to complex relationships. While several issues in the methodology and inferences from the results are still to be overcome, this review shows that the co-occurrence of ADHD with many psychiatric disorders and traits is genetically interpretable.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Estudo de Associação Genômica Ampla , Fenótipo , Fatores de Risco , Herança Multifatorial/genéticaRESUMO
Known comorbidities for Attention-Deficit Hyperactivity Disorder (ADHD) include conduct problems, substance use disorder and gaming. Comorbidity with conduct problems may increase the risk for substance use disorder and gaming in individuals with ADHD. The aim of the study was to build a causal model of the relationships between ADHD and comorbid conduct problems, and alcohol, nicotine, and other substance use, and gaming habits, while accounting for age and sex. We used a state-of-the-art causal discovery algorithm to analyze a case-only sample of 362 ADHD-diagnosed individuals in the ages 12-24 years. We found that conduct problem severity mediates between ADHD severity and nicotine use, but not with more severe alcohol or substance use. More severe ADHD-inattentive symptoms lead to more severe gaming habits. Furthermore, our model suggests that ADHD severity has no influence on severity of alcohol or other drug use. Our findings suggest that ADHD severity is a risk factor for nicotine use, and that this effect is fully mediated by conduct problem severity. Finally, ADHD-inattentive severity was a risk factor for gaming, suggesting that gaming dependence has a different causal pathway than substance dependence and should be treated differently. By identifying these intervention points, our model can aid both researchers and clinicians.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtorno da Conduta/psicologia , Transtorno de Adição à Internet/psicologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Jogos de Vídeo/psicologia , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Teorema de Bayes , Estudos de Casos e Controles , Criança , Pré-Escolar , Transtorno da Conduta/diagnóstico , Transtorno da Conduta/epidemiologia , Feminino , Humanos , Transtorno de Adição à Internet/diagnóstico , Transtorno de Adição à Internet/epidemiologia , Masculino , Fatores de Risco , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: To investigate the association between pediatric bipolar I (BP-I) disorder and conduct disorder (CD) using familial risk analysis. METHOD: We compared diagnoses in relatives of youth in four proband groups defined by the presence or absence of BP-I and CD: (1) probands with neither CD nor BP-I (probands: N = 550; relatives: N = 1656), (2) probands with CD and without BP-I (probands: N = 40; relatives: N = 127), (3) probands with BP-I and without CD (probands: N = 197; relatives: N = 579), and (4) probands with both CD and BP-I (probands: N = 176; relatives: N = 488). All subjects were evaluated with structured diagnostic interviews, and diagnoses of relatives were made blind to the diagnoses of probands. RESULTS: Relatives of probands with BP-I disorder had high rates of BP-I, and relatives of probands with CD had high rates of CD irrespective of the comorbidity with the other disorder. Relatives of probands with the combined condition of CD and BP-I had high rates of the combined condition. CONCLUSION: The finding of cosegregation between BP-I disorder and CD is consistent with the hypothesis that the combined condition represents a distinct subtype of either disorder.
Assuntos
Transtorno Bipolar/epidemiologia , Transtorno da Conduta/epidemiologia , Suscetibilidade a Doenças/epidemiologia , Família , Adolescente , Criança , Comorbidade , Feminino , Humanos , Masculino , Estudos Prospectivos , Medição de RiscoRESUMO
Longitudinal studies on the course of neurocognitive functioning of children with ADHD and their unaffected siblings are scarce. Also, it is unclear to what extent that course is related to ADHD outcomes. A carefully phenotyped large sample of 838 Caucasian participants (ADHD-combined type: n = 339, unaffected siblings: n = 271, controls: n = 228; mean age at baseline = 11.4 years, mean age at follow-up = 17.3 years, SD = 3.2) was used to investigate differences in the course of neurocognitive functioning of ADHD affected and unaffected siblings versus controls, and to investigate the relationship between neurocognitive change and ADHD outcomes. At baseline, an aggregated measure of overall neurocognitive functioning and eight neurocognitive measures of working memory, timing (speed/variability), motor control, and intelligence were investigated. Outcomes at follow-up were dimensional measures of ADHD symptom severity and the Kiddie-Global Assessment Scale (K-GAS) for overall functioning. At follow up, affected and unaffected siblings trended to, or fully caught up with performance levels of controls on four (44.4%) and five (55.6%) of the nine dependent variables, respectively. In contrast, performance in remaining key neurocognitive measures (i.e. verbal working memory, variability in responding) remained impaired at follow-up. Change in neurocognitive functioning was not related to ADHD outcomes. Our results question the etiological link between neurocognitive deficits and ADHD outcomes in adolescents and young adults.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Avaliação de Resultados em Cuidados de Saúde , Irmãos , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/terapia , Criança , Pré-Escolar , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/terapia , Feminino , Seguimentos , Humanos , Masculino , Adulto JovemRESUMO
Both neurocognitive deficits and schizophrenia are highly heritable. Genetic overlap between neurocognitive deficits and schizophrenia has been observed in both the general population and in the clinical samples. This study aimed to examine if the polygenic architecture of susceptibility to schizophrenia modified neurocognitive performance in schizophrenia patients. Schizophrenia polygenic risk scores (PRSs) were first derived from the Psychiatric Genomics Consortium (PGC) on schizophrenia, and then the scores were calculated in our independent sample of 1130 schizophrenia trios, who had PsychChip data and were part of the Schizophrenia Families from Taiwan project. Pseudocontrols generated from the nontransmitted parental alleles of the parents in these trios were compared with alleles in schizophrenia patients in assessing the replicability of PGC-derived susceptibility variants. Schizophrenia PRS at the P-value threshold (PT) of 0.1 explained 0.2% in the variance of disease status in this Han-Taiwanese samples, and the score itself had a P-value 0.05 for the association test with the disorder. Each patient underwent neurocognitive evaluation on sustained attention using the continuous performance test and executive function using the Wisconsin Card Sorting Test. We applied a structural equation model to construct the neurocognitive latent variable estimated from multiple measured indices in these 2 tests, and then tested the association between the PRS and the neurocognitive latent variable. Higher schizophrenia PRS generated at the PT of 0.1 was significantly associated with poorer neurocognitive performance with explained variance 0.5%. Our findings indicated that schizophrenia susceptibility variants modify the neurocognitive performance in schizophrenia patients.
Assuntos
Transtornos Neurocognitivos/genética , Esquizofrenia/genética , Adulto , Alelos , Função Executiva/fisiologia , Família , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Testes Neuropsicológicos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , TaiwanRESUMO
Sub-cortical volumetric differences were associated with attention-deficit/hyperactivity disorder (ADHD) in a recent multi-site, mega-analysis of 1713 ADHD persons and 1529 controls. As there was a wide range of effect sizes among the sub-cortical volumes, it is possible that selective neuronal vulnerability has a role in these volumetric losses. To address this possibility, we used data from Allen Brain Atlas to investigate variability in gene expression profiles between subcortical regions of typically developing brains. We tested the hypothesis that the expression of genes in a set of curated ADHD candidate genes and five a priori selected, biological pathways would be associated with the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) findings. Across the subcortical regions studied by ENIGMA, gene expression profiles for three pathways were significantly correlated with ADHD-associated volumetric reductions: apoptosis, oxidative stress and autophagy. These correlations were strong and significant for children with ADHD, but not for adults. Although preliminary, these data suggest that variability of structural brain anomalies in ADHD can be explained, in part, by the differential vulnerability of these regions to mechanisms mediating apoptosis, oxidative stress and autophagy.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Encéfalo/metabolismo , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/patologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Criança , Pré-Escolar , Feminino , Expressão Gênica , Estudos de Associação Genética , Humanos , Masculino , Metanálise como Assunto , Análise em Microsséries , Pessoa de Meia-Idade , Tamanho do Órgão , Transcriptoma , Adulto JovemRESUMO
Stimulant medication has long been effective in treating attention-deficit/hyperactivity disorder (ADHD) and is currently the first-line pharmacological treatment for children. Both methylphenidate and amphetamine modulate extracellular catecholamine levels through interaction with dopaminergic, adrenergic and serotonergic system components; it is therefore likely that catecholaminergic molecular components influence the effects of ADHD treatment. Using meta-analysis, we sought to identify predictors of pharmacotherapy to further the clinical implementation of personalized medicine. We identified 36 studies (3647 children) linking the effectiveness of methylphenidate treatment with DNA variants. Pooled-data revealed a statistically significant association between single nucleotide polymorphisms (SNPs) rs1800544 ADRA2A (odds ratio: 1.69; confidence interval: 1.12-2.55), rs4680 COMT (odds ratio (OR): 1.40; confidence interval: 1.04-1.87), rs5569 SLC6A2 (odds ratio: 1.73; confidence interval: 1.26-2.37) and rs28386840 SLC6A2 (odds ratio: 2.93; confidence interval: 1.76-4.90), and, repeat variants variable number tandem repeat (VNTR) 4 DRD4 (odds ratio: 1.66; confidence interval: 1.16-2.37) and VNTR 10 SLC6A3 (odds ratio: 0.74; confidence interval: 0.60-0.90), whereas the following variants were not statistically significant: rs1947274 LPHN3 (odds ratio: 0.95; confidence interval: 0.71-1.26), rs5661665 LPHN3 (odds ratio: 1.07; confidence interval: 0.84-1.37) and VNTR 7 DRD4 (odds ratio: 0.68; confidence interval: 0.47-1.00). Funnel plot asymmetry among SLC6A3 studies was identified and attributed largely to small study effects. Egger's regression test and Duval and Tweedie's 'trim and fill' were used to examine and correct for publication bias. These findings have major implications for advancing our therapeutic approach to childhood ADHD treatment.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Metilfenidato/farmacologia , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Biomarcadores Farmacológicos/sangue , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/metabolismo , Criança , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Genótipo , Humanos , Masculino , Repetições Minissatélites , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Farmacogenética , Polimorfismo de Nucleotídeo Único/genética , Receptores Adrenérgicos alfa 2/genética , Receptores Adrenérgicos alfa 2/metabolismo , Receptores de Dopamina D4/genética , Receptores de Dopamina D4/metabolismo , Resultado do TratamentoRESUMO
Identifying genetic variants contributing to attention-deficit/hyperactivity disorder (ADHD) is complicated by the involvement of numerous common genetic variants with small effects, interacting with each other as well as with environmental factors, such as stress exposure. Random forest regression is well suited to explore this complexity, as it allows for the analysis of many predictors simultaneously, taking into account any higher-order interactions among them. Using random forest regression, we predicted ADHD severity, measured by Conners' Parent Rating Scales, from 686 adolescents and young adults (of which 281 were diagnosed with ADHD). The analysis included 17 374 single-nucleotide polymorphisms (SNPs) across 29 genes previously linked to hypothalamic-pituitary-adrenal (HPA) axis activity, together with information on exposure to 24 individual long-term difficulties or stressful life events. The model explained 12.5% of variance in ADHD severity. The most important SNP, which also showed the strongest interaction with stress exposure, was located in a region regulating the expression of telomerase reverse transcriptase (TERT). Other high-ranking SNPs were found in or near NPSR1, ESR1, GABRA6, PER3, NR3C2 and DRD4. Chronic stressors were more influential than single, severe, life events. Top hits were partly shared with conduct problems. We conclude that random forest regression may be used to investigate how multiple genetic and environmental factors jointly contribute to ADHD. It is able to implicate novel SNPs of interest, interacting with stress exposure, and may explain inconsistent findings in ADHD genetics. This exploratory approach may be best combined with more hypothesis-driven research; top predictors and their interactions with one another should be replicated in independent samples.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Estresse Psicológico/genética , Telomerase/genética , Adolescente , Proteínas de Arabidopsis , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Liases Intramoleculares , Masculino , Sistema Hipófise-Suprarrenal/fisiopatologia , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologia , Adulto JovemRESUMO
Methylphenidate (MPH) is currently used to treat children with attention deficit hyperactivity disorder (ADHD). Several extended-release (ER) formulations characterized by a dual release process were developed to improve efficacy over an extended duration. In this study, a model-based approach using literature data was developed to: 1) evaluate the most efficient pharmacokinetic (PK) model to characterize the complex PK profile of MPH ER formulations; 2) provide PK endpoint metrics for comparing ER formulations; 3) define criteria for optimizing development of ER formulations using a convolution-based model linking in vitro release, in vivo release, and hour-by-hour behavioral ratings of ADHD symptoms; and 4) define an optimized trial design for assessing the activity of MPH in pediatric populations. The convolution-based model accurately described the complex PK profiles of a variety of ER MPH products, providing a natural framework for establishing an in vitro/in vivo correlation and for defining criteria for assessing comparative bioequivalence of MPH ER products.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Composição de Medicamentos , Metilfenidato/farmacocinética , Metilfenidato/uso terapêutico , Modelos Biológicos , Projetos de Pesquisa , Transtorno do Deficit de Atenção com Hiperatividade/sangue , Estimulantes do Sistema Nervoso Central/farmacocinética , Estimulantes do Sistema Nervoso Central/uso terapêutico , Criança , Preparações de Ação Retardada/uso terapêutico , Liberação Controlada de Fármacos , Humanos , Equivalência Terapêutica , Resultado do TratamentoRESUMO
BACKGROUND: Socioeconomic difficulties affect the cognitive and emotional development of children. However, the focus of prior studies has largely been on poverty and material hardship. This study expands on the existing literature by examining the impact of familial transient financial difficulties during infancy on long-term cognitive and behavioral outcomes. METHODS: The National Longitudinal Surveys of Youth (79) were used to assess the association between a transient drop in family income by 50% or more (called transient income decline or TID) during the first 3 years of life and later-life Peabody Individual Achievement Math and Reading scores and behavior problem index (BPI) scores (N = 8272-17 348; median assessment age = 9 years). A subsample of matched siblings (N = 2049-4238) was examined to tease out maternal and intra-familial effects. RESULTS: Exposure to TID predicted increased total and externalizing BPI scores (std. coefficients of 0.10 and 0.09, respectively, p < 0.01) in the overall sample. Among matched siblings, exposure to TID predicted increased total, externalizing, and internalizing BPI scores (std. coefficients of 0.27, 0.25, and 0.23, respectively, p < 0.01). CONCLUSION: Familial transient financial difficulties can have long-lasting behavioral effects for infants. The study identifies an early risk factor and at-risk children, thus providing insight into developing early intervention measures for infants to avoid long-term behavioral problems.
Assuntos
Desempenho Acadêmico/estatística & dados numéricos , Comportamento Infantil , Renda/estatística & dados numéricos , Comportamento Problema , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Matemática/estatística & dados numéricos , Irmãos , Estados Unidos/epidemiologia , VocabulárioRESUMO
BACKGROUND: A previous small study suggested that Brain Network Activation (BNA), a novel ERP-based brain network analysis, may have diagnostic utility in attention deficit hyperactivity disorder (ADHD). In this study we examined the diagnostic capability of a new advanced version of the BNA methodology on a larger population of adults with and without ADHD. METHOD: Subjects were unmedicated right-handed 18- to 55-year-old adults of both sexes with and without a DSM-IV diagnosis of ADHD. We collected EEG while the subjects were performing a response inhibition task (Go/NoGo) and then applied a spatio-temporal Brain Network Activation (BNA) analysis of the EEG data. This analysis produced a display of qualitative measures of brain states (BNA scores) providing information on cortical connectivity. This complex set of scores was then fed into a machine learning algorithm. RESULTS: The BNA analysis of the EEG data recorded during the Go/NoGo task demonstrated a high discriminative capacity between ADHD patients and controls (AUC = 0.92, specificity = 0.95, sensitivity = 0.86 for the Go condition; AUC = 0.84, specificity = 0.91, sensitivity = 0.76 for the NoGo condition). CONCLUSIONS: BNA methodology can help differentiate between ADHD and healthy controls based on functional brain connectivity. The data support the utility of the tool to augment clinical examinations by objective evaluation of electrophysiological changes associated with ADHD. Results also support a network-based approach to the study of ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Eletroencefalografia/métodos , Potenciais Evocados/fisiologia , Função Executiva/fisiologia , Inibição Psicológica , Rede Nervosa/fisiopatologia , Adolescente , Adulto , Eletroencefalografia/normas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Adulto JovemRESUMO
Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable childhood-onset neuropsychiatric condition, often persisting into adulthood. The genetic architecture of ADHD, particularly in adults, is largely unknown. We performed an exome-wide scan of adult ADHD using the Illumina Human Exome Bead Chip, which interrogates over 250 000 common and rare variants. Participants were recruited by the International Multicenter persistent ADHD CollaboraTion (IMpACT). Statistical analyses were divided into 3 steps: (1) gene-level analysis of rare variants (minor allele frequency (MAF)<1%); (2) single marker association tests of common variants (MAF⩾1%), with replication of the top signals; and (3) pathway analyses. In total, 9365 individuals (1846 cases and 7519 controls) were examined. Replication of the most associated common variants was attempted in 9847 individuals (2077 cases and 7770 controls) using fixed-effects inverse variance meta-analysis. With a Bonferroni-corrected significance level of 1.82E-06, our analyses of rare coding variants revealed four study-wide significant loci: 6q22.1 locus (P=4.46E-08), where NT5DC1 and COL10A1 reside; the SEC23IP locus (P=6.47E-07); the PSD locus (P=7.58E-08) and ZCCHC4 locus (P=1.79E-06). No genome-wide significant association was observed among the common variants. The strongest signal was noted at rs9325032 in PPP2R2B (odds ratio=0.81, P=1.61E-05). Taken together, our data add to the growing evidence of general signal transduction molecules (NT5DC1, PSD, SEC23IP and ZCCHC4) having an important role in the etiology of ADHD. Although the biological implications of these findings need to be further explored, they highlight the possible role of cellular communication as a potential core component in the development of both adult and childhood forms of ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Sequenciamento do Exoma , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo Genético/genética , Adulto , Encéfalo/metabolismo , Feminino , Loci Gênicos/genética , Variação Genética , Genótipo , Humanos , Masculino , Fases de Leitura Aberta/genéticaRESUMO
The glucocorticoid receptor plays a pivotal role in the brain's response to stress; a haplotype of functional polymorphisms in the NR3C1 gene encoding this receptor has been associated with attention-deficit hyperactivity disorder (ADHD). The serotonin transporter (5-HTT) gene polymorphism 5-HTTLPR is known to influence the relation between stress exposure and ADHD severity, which may be partly because of its reported effects on glucocorticoid levels. We therefore investigated if NR3C1 moderates the relation of stress exposure with ADHD severity and brain structure, and the potential role of 5-HTTLPR. Neuroimaging, genetic and stress exposure questionnaire data were available for 539 adolescents and young adults participating in the multicenter ADHD cohort study NeuroIMAGE (average age: 17.2 years). We estimated the effects of genetic variation in NR3C1 and 5-HTT, stress exposure and their interactions on ADHD symptom count and gray matter volume. We found that individuals carrying the ADHD risk haplotype of NR3C1 showed significantly more positive relation between stress exposure and ADHD severity than non-carriers. This gene-environment interaction was significantly stronger for 5-HTTLPR L-allele homozygotes than for S-allele carriers. These two- and three-way interactions were reflected in the gray matter volume of the cerebellum, parahippocampal gyrus, intracalcarine cortex and angular gyrus. Our findings illustrate how genetic variation in the stress response pathway may influence the effects of stress exposure on ADHD severity and brain structure. The reported interplay between NR3C1 and 5-HTT may further explain some of the heterogeneity between studies regarding the role of these genes and hypothalamic-pituitary-adrenal axis activity in ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Encéfalo/anatomia & histologia , Encéfalo/fisiopatologia , Receptores de Glucocorticoides/genética , Estresse Psicológico/genética , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/patologia , Estudos de Coortes , Feminino , Frequência do Gene , Interação Gene-Ambiente , Variação Genética , Haplótipos , Humanos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Masculino , Sistema Hipófise-Suprarrenal/fisiopatologia , Polimorfismo de Nucleotídeo Único , Receptores de Glucocorticoides/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Estresse Psicológico/metabolismo , Adulto JovemRESUMO
The adult form of attention-deficit/hyperactivity disorder has a prevalence of up to 5% and is the most severe long-term outcome of this common disorder. Family studies in clinical samples as well as twin studies suggest a familial liability and consequently different genes were investigated in association studies. Pharmacotherapy with methylphenidate (MPH) seems to be the first-line treatment of choice in adults with attention-deficit hyperactive disorder (ADHD) and some studies were conducted on the genes influencing the response to this drug. Finally some peripheral biomarkers were identified in ADHD adult patients. We believe this work is the first systematic review and meta-analysis of candidate gene association studies, pharmacogenetic and biochemical (metabolomics) studies performed in adults with ADHD to identify potential genetic, predictive and peripheral markers linked specifically to ADHD in adults. After screening 5129 records, we selected 87 studies of which 61 were available for candidate gene association studies, 5 for pharmacogenetics and 21 for biochemical studies. Of these, 15 genetic, 2 pharmacogenetic and 6 biochemical studies were included in the meta-analyses. We obtained an association between adult ADHD and the gene BAIAP2 (brain-specific angiogenesis inhibitor 1-associated protein 2), even after Bonferroni correction, with any heterogeneity in effect size and no publication bias. If we did not apply the Bonferroni correction, a trend was found for the carriers allele 9R of dopamine transporter SLC6A3 40 bp variable tandem repeat polymorphism (VNTR) and for 6/6 homozygotes of SLC6A3 30 bp VNTR. Negative results were obtained for the 9-6 haplotype, the dopamine receptor DRD4 48 bp VNTR, and the enzyme COMT SNP rs4680. Concerning pharmacogenetic studies, no association was found for the SLC6A3 40 bp and response to MPH with only two studies selected. For the metabolomics studies, no differences between ADHD adults and controls were found for salivary cortisol, whereas lower serum docosahexaenoic acid (DHA) levels were found in ADHD adults. This last association was significant even after Bonferroni correction and in absence of heterogeneity. Other polyunsaturated fatty acids (PUFAs) such as AA (arachidonic acid), EPA (eicosapentaenoic acid) and DyLA (dihomogammalinolenic acid) levels were not different between patients and controls. No publication biases were observed for these markers. Genes linked to dopaminergic, serotoninergic and noradrenergic signaling, metabolism (DBH, TPH1, TPH2, DDC, MAOA, MAOB, BCHE and TH), neurodevelopment (BDNF and others), the SNARE system and other forty genes/proteins related to different pathways were not meta-analyzed due to insufficient data. In conclusion, we found that there were not enough genetic, pharmacogenetic and biochemical studies of ADHD in adults and that more investigations are needed. Moreover we confirmed a significant role of BAIAP2 and DHA in the etiology of ADHD exclusively in adults. Future research should be focused on the replication of these findings and to assess their specificity for ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas do Tecido Nervoso/genética , Adulto , Alelos , Biomarcadores/sangue , Ácidos Docosa-Hexaenoicos/sangue , Ácidos Docosa-Hexaenoicos/genética , Ácidos Docosa-Hexaenoicos/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Genótipo , Humanos , Masculino , Metilfenidato/uso terapêutico , Repetições Minissatélites/genética , Proteínas do Tecido Nervoso/metabolismo , Farmacogenética , Polimorfismo Genético , Receptores de Dopamina D4/genéticaRESUMO
Little is known about the causes of individual differences in reward sensitivity. We investigated gene-environment interactions (GxE) on behavioral and neural measures of reward sensitivity, in light of the differential susceptibility theory. This theory states that individuals carrying plasticity gene variants will be more disadvantaged in negative, but more advantaged in positive environments. Reward responses were assessed during a monetary incentive delay task in 178 participants with and 265 without attention-deficit/hyperactivity disorder (ADHD), from N=261 families. We examined interactions between variants in candidate plasticity genes (DAT1, 5-HTT and DRD4) and social environments (maternal expressed emotion and peer affiliation). HTTLPR short allele carriers showed the least reward speeding when exposed to high positive peer affiliation, but the most when faced with low positive peer affiliation or low maternal warmth. DAT1 10-repeat homozygotes displayed similar GxE patterns toward maternal warmth on general task performance. At the neural level, DRD4 7-repeat carriers showed the least striatal activation during reward anticipation when exposed to high maternal warmth, but the most when exposed to low warmth. Findings were independent of ADHD severity. Our results partially confirm the differential susceptibility theory and indicate the importance of positive social environments in reward sensitivity and general task performance for persons with specific genotypes.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Comportamento Materno , Grupo Associado , Receptores de Dopamina D4/genética , Recompensa , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adolescente , Comportamento do Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Estudos de Casos e Controles , Variações do Número de Cópias de DNA , Feminino , Neuroimagem Funcional , Frequência do Gene , Interação Gene-Ambiente , Predisposição Genética para Doença , Homozigoto , Humanos , Imageamento por Ressonância Magnética , Masculino , Neostriado/diagnóstico por imagem , Neostriado/fisiopatologia , Plasticidade Neuronal/genética , Adulto JovemRESUMO
The rs1076560 polymorphism of DRD2 (encoding dopamine receptor D2) is associated with alternative splicing and cognitive functioning; however, a mechanistic relationship to schizophrenia has not been shown. Here, we demonstrate that rs1076560(T) imparts a small but reliable risk for schizophrenia in a sample of 616 affected families and five independent replication samples totaling 4017 affected and 4704 unaffected individuals (odds ratio=1.1; P=0.004). rs1076560(T) was associated with impaired verbal fluency and comprehension in schizophrenia but improved performance among healthy comparison subjects. rs1076560(T) also associated with lower D2 short isoform expression in postmortem brain. rs1076560(T) disrupted a binding site for the splicing factor ZRANB2, diminished binding affinity between DRD2 pre-mRNA and ZRANB2 and abolished the ability of ZRANB2 to modulate short:long isoform-expression ratios of DRD2 minigenes in cell culture. Collectively, this work implicates rs1076560(T) as one possible risk factor for schizophrenia in the Han Chinese population, and suggests molecular mechanisms by which it may exert such influence.
Assuntos
Receptores de Dopamina D2/genética , Esquizofrenia/genética , Adulto , Alelos , Processamento Alternativo/genética , Encéfalo/metabolismo , China , Cognição/fisiologia , Etnicidade/genética , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Precursores de RNA/metabolismo , Splicing de RNA , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Receptores de Dopamina D2/metabolismo , Fatores de Risco , Esquizofrenia/metabolismoRESUMO
A strong motivation for undertaking psychiatric gene discovery studies is to provide novel insights into unknown biology. Although attention-deficit hyperactivity disorder (ADHD) is highly heritable, and large, rare copy number variants (CNVs) contribute to risk, little is known about its pathogenesis and it remains commonly misunderstood. We assembled and pooled five ADHD and control CNV data sets from the United Kingdom, Ireland, United States of America, Northern Europe and Canada. Our aim was to test for enrichment of neurodevelopmental gene sets, implicated by recent exome-sequencing studies of (a) schizophrenia and (b) autism as a means of testing the hypothesis that common pathogenic mechanisms underlie ADHD and these other neurodevelopmental disorders. We also undertook hypothesis-free testing of all biological pathways. We observed significant enrichment of individual genes previously found to harbour schizophrenia de novo non-synonymous single-nucleotide variants (SNVs; P=5.4 × 10(-4)) and targets of the Fragile X mental retardation protein (P=0.0018). No enrichment was observed for activity-regulated cytoskeleton-associated protein (P=0.23) or N-methyl-D-aspartate receptor (P=0.74) post-synaptic signalling gene sets previously implicated in schizophrenia. Enrichment of ADHD CNV hits for genes impacted by autism de novo SNVs (P=0.019 for non-synonymous SNV genes) did not survive Bonferroni correction. Hypothesis-free testing yielded several highly significantly enriched biological pathways, including ion channel pathways. Enrichment findings were robust to multiple testing corrections and to sensitivity analyses that excluded the most significant sample. The findings reveal that CNVs in ADHD converge on biologically meaningful gene clusters, including ones now established as conferring risk of other neurodevelopmental disorders.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Psiquiatria Biológica/métodos , Adolescente , Transtorno Autístico/genética , Canadá , Criança , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Bases de Dados de Ácidos Nucleicos , Europa (Continente) , Feminino , Estudos de Associação Genética/métodos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Irlanda , Masculino , Transtornos do Neurodesenvolvimento/genética , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Reino UnidoRESUMO
BACKGROUND: The Harvard Adolescent Family High Risk (FHR) Study examined multiple domains of function in young relatives of individuals diagnosed with schizophrenia to identify precursors of the illness. One such area is motor performance, which is deviant in people with schizophrenia and in children at risk for schizophrenia, usually offspring. The present study assessed accuracy of motor performance and degree of lateralization in FHR adolescents and young adults. METHODS: Subjects were 33 non-psychotic, first-degree relatives of individuals diagnosed with schizophrenia, and 30 non-psychotic comparison subjects (NpC), ranging in age from 13 to 25 who were compared using a line-drawing task. RESULTS: FHR individuals exhibited less precise and coordinated line drawing but greater degree of lateralization than controls. Performance on the linedrawing task was correlated with degree of genetic loading, a possible predictor of higher risk for schizophrenia in the pedigree. CONCLUSIONS: The observation of increased motor deviance and increased lateralization in FHR can be utilized in identification and initiation of the treatment in those at high risk in order to prevent or delay the full manifestation of this devastating condition. The use of a rigorously quantified measure is likely to add to the sensitivity of measuring motor performance, especially when impairments may be subtle.
Assuntos
Saúde da Família , Transtornos Psicomotores , Esquizofrenia/complicações , Adolescente , Adulto , Feminino , Lateralidade Funcional , Humanos , Masculino , Testes Neuropsicológicos , Transtornos Psicomotores/diagnóstico , Transtornos Psicomotores/etiologia , Transtornos Psicomotores/genética , Risco , Esquizofrenia/genética , Adulto JovemRESUMO
BACKGROUND: Although risk for psychosis in velocardiofacial (22q11.2 deletion) syndrome (VCFS) is well established, the cognitive and familial factors that moderate that risk are poorly understood. METHOD: A total of 75 youth with VCFS were assessed at three time points, at 3-year intervals. Time 1 (T1) psychiatric risk was assessed with the Behavior Assessment System for Children (BASC). Data reduction of BASC scores yielded avoidance-anxiety and dysregulation factors. Time 2 (T2) neuropsychological and family function and time 3 (T3) prodromal/overt psychosis were assessed. Poisson regression models tested associations between T3 positive prodromal symptoms/overt psychosis and T1 psychiatric risk, T2 cognitive and familial factors, and their interactions. RESULTS: T1 avoidance-anxiety ratings predicted T3 prodromal/overt psychosis. T2 verbal learning scores moderated this association, such that individuals with low avoidance-anxiety scores and stronger verbal learning skills were the least likely to demonstrate prodromal/overt psychosis at T3. Low scores on a T2 visual vigilance task also predicted T3 prodromal/overt psychosis, independently of the effect of T1 avoidance-anxiety scores. T1 dysregulation scores did not predict T3 prodromal/overt psychosis in a linear manner. Instead, the association between dysregulation and prodromal/overt psychosis was amplified by T2 levels of family organization, such that individuals with low dysregulation scores and low family organization scores were the most likely to exhibit T3 prodromal/overt psychosis. CONCLUSIONS: Significant moderators of psychiatric risk in VCFS include verbal learning skills as well as levels of family organization, carrying implications for early identification and preventative treatment of youth with VCFS at highest risk for psychosis.