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1.
Eur Neuropsychopharmacol ; 29(6): 795-802, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31085060

RESUMO

Emotional lability is strongly associated with Attention Deficit Hyperactivity Disorder (ADHD), represents a major source of impairment and predicts poor clinical outcome in ADHD. Given that no specific genes with a role in the co-occurrence of both conditions have been described, we conducted a GWAS of emotional lability in 563 adults with ADHD. Despite not reaching genome-wide significance, the results highlighted genes related with neurotransmission, cognitive function and a wide range of psychiatric disorders that have emotional lability as common clinical feature. By constructing polygenic risk scores on mood instability in the UK Biobank sample and assessing their association with emotional lability in our clinical dataset, we found suggestive evidence of common genetic variation contributing to emotional lability in general population and in clinically diagnosed ADHD. Although not conclusive, these tentative results are in agreement with previous studies that suggest emotion dysregulation as a transdiagnostic construct and highlight the need for further investigation to disentangle the genetic basis of mood instability in ADHD and co-occurring psychiatric disorders.

2.
Transl Psychiatry ; 9(1): 42, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696812

RESUMO

Genetic factors are strongly implicated in the susceptibility to develop externalizing syndromes such as attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder, conduct disorder, and substance use disorder (SUD). Variants in the ADGRL3 (LPHN3) gene predispose to ADHD and predict ADHD severity, disruptive behaviors comorbidity, long-term outcome, and response to treatment. In this study, we investigated whether variants within ADGRL3 are associated with SUD, a disorder that is frequently co-morbid with ADHD. Using family-based, case-control, and longitudinal samples from disparate regions of the world (n = 2698), recruited either for clinical, genetic epidemiological or pharmacogenomic studies of ADHD, we assembled recursive-partitioning frameworks (classification tree analyses) with clinical, demographic, and ADGRL3 genetic information to predict SUD susceptibility. Our results indicate that SUD can be efficiently and robustly predicted in ADHD participants. The genetic models used remained highly efficient in predicting SUD in a large sample of individuals with severe SUD from a psychiatric institution that were not ascertained on the basis of ADHD diagnosis, thus identifying ADGRL3 as a risk gene for SUD. Recursive-partitioning analyses revealed that rs4860437 was the predominant predictive variant. This new methodological approach offers novel insights into higher order predictive interactions and offers a unique opportunity for translational application in the clinical assessment of patients at high risk for SUD.


Assuntos
Predisposição Genética para Doença , Receptores Acoplados a Proteínas-G/genética , Receptores de Peptídeos/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Estudos Longitudinais , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adulto Jovem
3.
Mol Psychiatry ; 2019 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-30610198

RESUMO

Attention-deficit/hyperactivity disorder (ADHD) is a severely impairing neurodevelopmental disorder with a prevalence of 5% in children and adolescents and of 2.5% in adults. Comorbid conditions in ADHD play a key role in symptom progression, disorder course and outcome. ADHD is associated with a significantly increased risk for substance use, abuse and dependence. ADHD and cannabis use are partly determined by genetic factors; the heritability of ADHD is estimated at 70-80% and of cannabis use initiation at 40-48%. In this study, we used summary statistics from the largest available meta-analyses of genome-wide association studies (GWAS) of ADHD (n = 53,293) and lifetime cannabis use (n = 32,330) to gain insights into the genetic overlap and causal relationship of these two traits. We estimated their genetic correlation to be r2 = 0.29 (P = 1.63 × 10-5) and identified four new genome-wide significant loci in a cross-trait analysis: two in a single variant association analysis (rs145108385, P = 3.30 × 10-8 and rs4259397, P = 4.52 × 10-8) and two in a gene-based association analysis (WDPCP, P = 9.67 × 10-7 and ZNF251, P = 1.62 × 10-6). Using a two-sample Mendelian randomization approach we found support that ADHD is causal for lifetime cannabis use, with an odds ratio of 7.9 for cannabis use in individuals with ADHD in comparison to individuals without ADHD (95% CI (3.72, 15.51), P = 5.88 × 10-5). These results substantiate the temporal relationship between ADHD and future cannabis use and reinforce the need to consider substance misuse in the context of ADHD in clinical interventions.

4.
Neuropsychopharmacology ; 44(5): 890-897, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30568281

RESUMO

Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders in childhood and persists into adulthood in 40-65% of cases. Given the polygenic and heterogeneous architecture of the disorder and the limited overlap between genetic studies, there is a growing interest in epigenetic mechanisms, such as microRNAs, that modulate gene expression and may contribute to the phenotype. We attempted to clarify the role of microRNAs in ADHD at a molecular level through the first genome-wide integrative study of microRNA and mRNA profiles in peripheral blood mononuclear cells of medication-naive individuals with ADHD and healthy controls. We identified 79 microRNAs showing aberrant expression levels in 56 ADHD cases and 69 controls, with three of them, miR-26b-5p, miR-185-5p, and miR-191-5p, being highly predictive for diagnostic status in an independent dataset of 44 ADHD cases and 46 controls. Investigation of downstream microRNA-mediated mechanisms underlying the disorder, which was focused on differentially expressed, experimentally validated target genes of the three highly predictive microRNAs, provided evidence for aberrant myo-inositol signaling in ADHD and indicated an enrichment of genes involved in neurological disease and psychological disorders. Our comprehensive study design reveals novel microRNA-mRNA expression profiles aberrant in ADHD, provides novel insights into microRNA-mediated mechanisms contributing to the disorder, and highlights promising candidate peripheral biomarkers.

5.
Addiction ; 113(11): 2073-2086, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30003630

RESUMO

BACKGROUND AND AIMS: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes, including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants. METHODS: A twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome-wide association meta-analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals. RESULTS: The twin-based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19-60%]. Shared and unique environmental factors explained 39% (95% CI = 20-56%) and 22% (95% CI = 16-29%). The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P < 5E-08. All five SNPs are in high linkage disequilibrium (LD) (r2  > 0.8), with the strongest association at the intronic variant rs1574587 (P = 4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P = 1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant. CONCLUSION: Age at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.

6.
Drug Alcohol Depend ; 187: 358-362, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29715653

RESUMO

BACKGROUND: Substance dependence is a chronic and relapsing disorder explained by genetic and environmental risk factors. The aim of our study is to replicate previous genome-wide significant (GWS) hits identified in substance dependence in general or in cocaine dependence in particular using an independent sample from Spain. METHODS: We evaluated, in a Spanish sample of 1711 subjects with substance dependence (1011 of them cocaine dependent) and 1719 control individuals, three SNPs identified as GWS in previous studies: rs1868152 and rs2952621 (located near LINC02052 and LINC01854, respectively), associated with substance dependence, and rs2629540 (in the first intron of FAM53B), associated with cocaine dependence. RESULTS: We replicated the association between rs2952621 and substance dependence under the dominant model (P = 0.020), with the risk allele (T) being the same in our sample and in those two reported previously. We then performed a meta-analysis of the two samples used in the original study that reported the association of rs2952621 with substance dependence (Collaborative Studies on Genetics of Alcoholism (COGA) and Study of Addiction: Genetics and Environment (SAGE)) together with our Spanish sample. The meta-analysis of 3747 cases and 4043 controls confirmed the association (OR = 1.26, 95% CI = 1.15-1.39). CONCLUSIONS: The rs2952621 variant, located downstream from the yet uncharacterized gene LINC01854, is associated with substance dependence in our Spanish sample. Further research is needed to understand its contribution to the susceptibility to substance dependence.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/genética , Predisposição Genética para Doença , Transtornos Relacionados ao Uso de Substâncias/genética , Meio Ambiente , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Recidiva , Fatores de Risco , Espanha
7.
Rev. neurol. (Ed. impr.) ; 66(supl.1): S109-S114, mar. 2018. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-171900

RESUMO

Introducción. El trastorno por déficit de atención/hiperactividad (TDAH) presenta una etiología compleja, atribuida principalmente a múltiples genes de susceptibilidad y factores ambientales. No obstante, los estudios genéticos de asociación han sido inconsistentes, identificando variantes genéticas de efecto moderado que explican una pequeña proporción de la heredabilidad estimada del trastorno (< 10%). Recientes estudios sugieren que la microbiota intestinal y la dieta desempeñan un papel importante en el desarrollo y los síntomas de diferentes trastornos mentales. Sin embargo, en la actualidad no existe una claridad absoluta al respecto. El presente proyecto propone un abordaje alternativo para identificar mecanismos a través de los cuales el ecosistema microbiano intestinal y la dieta podrían contribuir a la presencia del TDAH. Objetivo. Identificar biomarcadores para el TDAH a través del estudio de la microbiota intestinal. Sujetos y métodos. Estudio transversal de pacientes adultos con TDAH (n = 100) y de individuos control (n = 100). En ambos grupos se tomarán medidas de evaluación de TDAH y hábitos alimentarios. Se obtendrán muestras fecales para la extracción del ADN bacteriano, que permitirán caracterizar la microbiota intestinal de los participantes, para posteriormente realizar un estudio de asociación metagenómico e intentar correlacionar la composición bacteriana intestinal con subtipos clínicos del trastorno. Resultados y conclusiones. Se espera que la comparación de los perfiles de microbiota intestinal entre sujetos con TDAH y controles ayude a explicar la heterogeneidad clínica del trastorno e identificar nuevos mecanismos implicados en su desarrollo (AU)


Introduction. Attention deficit hyperactivity disorder (ADHD) has a complex aetiology, mainly attributed to a number of susceptibility genes and environmental factors. Genetic association studies, however, have been inconsistent and have identified genetic variants with a moderate effect that explain a small proportion of the estimated inheritability of the disorder (< 10%). Recent studies suggest that the gut microbiota and diet play an important role in the development and symptoms of different mental disorders. Nevertheless, no clear evidence exists on the issue. This project proposes an alternative approach to identify mechanisms by which the intestinal microbial ecosystem and diet could contribute to the presence of ADHD. Aim. To identify biomarkers for ADHD by examining the gut microbiota. Subjects and methods. We conducted a cross-sectional study of adult patients with ADHD (n = 100) and control subjects (n = 100). Measures of ADHD evaluation and eating habits were performed in both groups. Samples of faecal material were obtained from which to extract bacterial DNA, then used to characterise the participants’ gut microbiota. A metagenomics association study was later performed to attempt to correlate the bacterial composition of the intestine with the clinical subtypes of the disorder. Results and conclusions. Comparing the gut microbiota profiles of subjects with ADHD and controls is expected to help account for the clinical heterogeneity of the disorder and identify new mechanisms involved in its development (AU)


Assuntos
Humanos , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Microbioma Gastrointestinal , Biomarcadores/análise , Transtornos do Neurodesenvolvimento/diagnóstico , Predisposição Genética para Doença , Fatores de Risco , Estudos Transversais
8.
Sci Rep ; 8(1): 1881, 2018 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-29382897

RESUMO

Methylphenidate (MPH) is the most frequently used pharmacological treatment in children with attention-deficit/hyperactivity disorder (ADHD). However, a considerable interindividual variability exists in clinical outcome. Thus, we performed a genome-wide association study of MPH efficacy in 173 ADHD paediatric patients. Although no variant reached genome-wide significance, the set of genes containing single-nucleotide polymorphisms (SNPs) nominally associated with MPH response (P < 0.05) was significantly enriched for candidates previously studied in ADHD or treatment outcome. We prioritised the nominally significant SNPs by functional annotation and expression quantitative trait loci (eQTL) analysis in human brain, and we identified 33 SNPs tagging cis-eQTL in 32 different loci (referred to as eSNPs and eGenes, respectively). Pathway enrichment analyses revealed an over-representation of genes involved in nervous system development and function among the eGenes. Categories related to neurological diseases, psychological disorders and behaviour were also significantly enriched. We subsequently meta-analysed the association with clinical outcome for the 33 eSNPs across the discovery sample and an independent cohort of 189 ADHD adult patients (target sample) and we detected 15 suggestive signals. Following this comprehensive strategy, our results provide a better understanding of the molecular mechanisms implicated in MPH treatment effects and suggest promising candidates that may encourage future studies.

9.
Sci Rep ; 7(1): 5407, 2017 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-28710364

RESUMO

Attention Deficit Hyperactivity Disorder (ADHD) is a common childhood-onset neurodevelopmental condition characterized by pervasive impairment of attention, hyperactivity, and/or impulsivity that can persist into adulthood. The aetiology of ADHD is complex and multifactorial and, despite the wealth of evidence for its high heritability, genetic studies have provided modest evidence for the involvement of specific genes and have failed to identify consistent and replicable results. Due to the lack of robust findings, we performed gene-wide and pathway enrichment analyses using pre-existing GWAS data from 607 persistent ADHD subjects and 584 controls, produced by our group. Subsequently, expression profiles of genes surpassing a follow-up threshold of P-value < 1e-03 in the gene-wide analyses were tested in peripheral blood mononucleated cells (PBMCs) of 45 medication-naive adults with ADHD and 39 healthy unrelated controls. We found preliminary evidence for genetic association between RNF122 and ADHD and for its overexpression in adults with ADHD. RNF122 encodes for an E3 ubiquitin ligase involved in the proteasome-mediated processing, trafficking, and degradation of proteins that acts as an essential mediator of the substrate specificity of ubiquitin ligation. Thus, our findings support previous data that place the ubiquitin-proteasome system as a promising candidate for its involvement in the aetiology of ADHD.

10.
Rev Neurosci ; 28(5): 499-508, 2017 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-28306543

RESUMO

Several neurobiological factors are related to opiate-use disorder (OUD), and among them, neurotrophins have a relevant role. Brain-derived neurotrophic factor (BDNF) is a central neurotrophin involved in many neuronal processes, and it has been related to several psychiatric diseases and addictive disorders. BDNF can be measured in plasma and serum; its levels may reflect BDNF concentrations in the central nervous system (CNS) and, indirectly, CNS processes. Hence, peripheral BDNF could be a biomarker in clinical practice. This manuscript explores the findings about peripheral BDNF and OUD in humans. Opiates induce neurotoxicity in the CNS, which may be correlated with modifications in BDNF expression. Thus, basal levels of peripheral BDNF in OUD patients may be altered, which could be modified with abstinence. Also, opiates may modify epigenetic processes that may be associated with peripheral concentrations of BDNF, and in this line, withdrawal could reflect recovering processes in the CNS. Additionally, treatment modifies the peripheral concentrations of BDNF, but the clinical implications of those changes are yet not elucidated. No specific conclusion can be performed and more investigation in this area is necessary to elucidate the real potential of peripheral BDNF as a biomarker.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Transtornos Relacionados ao Uso de Opioides/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Epigênese Genética , Humanos , Transtornos Relacionados ao Uso de Opioides/sangue , Transtornos Relacionados ao Uso de Opioides/genética , Transtornos Relacionados ao Uso de Opioides/terapia
11.
Am J Med Genet B Neuropsychiatr Genet ; 171(5): 733-47, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27021288

RESUMO

Aggressiveness is a behavioral trait that has the potential to be harmful to individuals and society. With an estimated heritability of about 40%, genetics is important in its development. We performed an exploratory genome-wide association (GWA) analysis of childhood aggressiveness in attention deficit hyperactivity disorder (ADHD) to gain insight into the underlying biological processes associated with this trait. Our primary sample consisted of 1,060 adult ADHD patients (aADHD). To further explore the genetic architecture of childhood aggressiveness, we performed enrichment analyses of suggestive genome-wide associations observed in aADHD among GWA signals of dimensions of oppositionality (defiant/vindictive and irritable dimensions) in childhood ADHD (cADHD). No single polymorphism reached genome-wide significance (P < 5.00E-08). The strongest signal in aADHD was observed at rs10826548, within a long noncoding RNA gene (beta = -1.66, standard error (SE) = 0.34, P = 1.07E-06), closely followed by rs35974940 in the neurotrimin gene (beta = 3.23, SE = 0.67, P = 1.26E-06). The top GWA SNPs observed in aADHD showed significant enrichment of signals from both the defiant/vindictive dimension (Fisher's P-value = 2.28E-06) and the irritable dimension in cADHD (Fisher's P-value = 0.0061). In sum, our results identify a number of biologically interesting markers possibly underlying childhood aggressiveness and provide targets for further genetic exploration of aggressiveness across psychiatric disorders. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.


Assuntos
Agressão/fisiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Adolescente , Adulto , Agressão/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Criança , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética
12.
Eur Arch Psychiatry Clin Neurosci ; 266(4): 307-16, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26182893

RESUMO

Current knowledge suggests that borderline personality disorder (BPD) results from the interaction between genetic and environmental factors. Research has mainly focused on monoaminergic genetic variants and their modulation by traumatic events, especially those occurring during childhood. However, to the best of our knowledge, there are no studies on the genetics of hypothalamus-pituitary-adrenal (HPA) axis, despite its vulnerability to early stress and its involvement in BPD pathogenesis. The aim of this study was to investigate the contribution of genetic variants in the HPA axis and to explore the modulating effect of childhood trauma in a large sample of BPD patients and controls. DNA was obtained from a sample of 481 subjects with BPD and 442 controls. Case-control differences in allelic frequencies of 47 polymorphisms in 10 HPA axis genes were analysed. Modulation of genetic associations by the presence of childhood trauma was also investigated by dividing the sample into three groups: BPD with trauma, BPD without trauma and controls. Two FKBP5 polymorphisms (rs4713902-C and rs9470079-A) showed significant associations with BPD. There were also associations between BPD and haplotype combinations of the genes FKBP5 and CRHR1. Two FKBP5 alleles (rs3798347-T and rs10947563-A) were more frequent in BPD subjects with history of physical abuse and emotional neglect and two CRHR2 variants (rs4722999-C and rs12701020-C) in BPD subjects with sexual and physical abuse. Our findings suggest a contribution of HPA axis genetic variants to BPD pathogenesis and reinforce the hypothesis of the modulating effect of childhood trauma in the development of this disorder.


Assuntos
Transtorno da Personalidade Borderline , Maus-Tratos Infantis/psicologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Adulto , Transtorno da Personalidade Borderline/etiologia , Transtorno da Personalidade Borderline/genética , Transtorno da Personalidade Borderline/patologia , Estudos de Casos e Controles , Criança , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Receptores de Hormônio Liberador da Corticotropina/genética , Proteínas de Ligação a Tacrolimo/genética , Adulto Jovem
13.
Am J Med Genet B Neuropsychiatr Genet ; 168(6): 480-491, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26174753

RESUMO

We performed a case-control association study in persistent ADHD considering eight candidate genes (DRD4, DAT1/SLC6A3, COMT, ADRA2A, CES1, CYP2D6, LPHN3, and OPRM1) and found additional evidence for the involvement of the Dup 120bp and VNTR 48bp functional variants within the dopamine receptor DRD4 gene in the etiology of adult ADHD. We subsequently investigated the interaction of stressful life events with these two DRD4 polymorphisms, and the impact of such events on the severity of ADHD symptomatology. The gene-by-environment analysis revealed an independent effect of stressful experiences on the severity of persistent ADHD, and a gene-by-environment interaction on the inattentive dimension of the disorder, where non carriers of the Dup 120bp (L) - VNTR 48bp (7R) haplotype were more sensitive to environmental adversity than carriers. These results are in agreement with previous works reporting a relationship between DRD4 and the effect of adverse experiences, which may explain the discordant findings in previous genetic studies and strengthen the importance of gene-by-environment interactions on the severity of ADHD. © 2015 Wiley Periodicals, Inc.

14.
Am J Med Genet B Neuropsychiatr Genet ; 168(6): 459-470, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26174813

RESUMO

Attention deficit is one of the core symptoms of the attention-deficit/hyperactivity disorder (ADHD). However, the specific genetic variants that may be associated with attention function in adult ADHD remain largely unknown. The present study aimed to identifying SNPs associated with attention function in adult ADHD and tested whether these associations were enriched for specific biological pathways. Commissions, hit-reaction time (HRT), the standard error of HRT (HRTSE), and intraindividual coefficient variability (ICV) of the Conners Continuous Performance Test (CPT-II) were assessed in 479 unmedicated adult ADHD individuals. A Genome-Wide Association Study (GWAS) was conducted for each outcome and, subsequently, gene set enrichment analyses were performed. Although no SNPs reached genome-wide significance (P < 5E-08), 27 loci showed suggestive evidence of association with the CPT outcomes (P < E-05). The most relevant associated SNP was located in the SORCS2 gene (P = 3.65E-07), previously associated with bipolar disorder (BP), Alzheimer disease (AD), and brain structure in elderly individuals. We detected other genes suggested to be involved in synaptic plasticity, cognitive function, neurological and neuropsychiatric disorders, and smoking behavior such as NUAK1, FGF20, NETO1, BTBD9, DLG2, TOP3B, and CHRNB4. Also, several of the pathways nominally associated with the CPT outcomes are relevant for ADHD such as the ubiquitin proteasome, neurodegenerative disorders, axon guidance, and AD amyloid secretase pathways. To our knowledge, this is the first GWAS and pathway analysis of attention function in patients with persistent ADHD. Overall, our findings reinforce the conceptualization of attention function as a potential endophenotype for studying the molecular basis of adult ADHD. © 2015 Wiley Periodicals, Inc.

15.
Psychiatry Res ; 229(1-2): 589-92, 2015 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-26216165

RESUMO

This study investigated the possible association of 40 polymorphisms within 4 noradrenergic genes with BPD risk and the modulating effect of childhood trauma on these associations in 481 BPD subjects and 442 controls. COMT rs5993882, DBH rs77905 and SLC6A2 rs1814270 showed associations with BPD, which were modulated by childhood trauma. However, none of these findings survived Bonferroni correction. Further investigation is needed to clarify the involvement of these genes in BPD pathogenesis.


Assuntos
Transtorno da Personalidade Borderline/epidemiologia , Transtorno da Personalidade Borderline/genética , Catecol O-Metiltransferase/genética , Maus-Tratos Infantis , Estudos de Associação Genética/métodos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Adulto , Transtorno da Personalidade Borderline/psicologia , Criança , Maus-Tratos Infantis/psicologia , Dopamina beta-Hidroxilase/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Regiões Promotoras Genéticas/genética , Estudos Retrospectivos
16.
Am J Med Genet B Neuropsychiatr Genet ; 168(6): 445-458, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26086921

RESUMO

Attention deficit/ hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder featuring complex genetics with common and rare variants contributing to disease risk. In a high proportion of cases, ADHD does not remit during adolescence but persists into adulthood. Several studies suggest that NOS1, encoding nitric oxide synthase I, producing the gaseous neurotransmitter NO, is a candidate gene for (adult) ADHD. We here extended our analysis by increasing the original sample, adding two further samples from Norway and Spain, and conducted subgroup and co-morbidity analysis. Our previous finding held true in the extended sample, and also meta-analysis demonstrated an association of NOS1 ex1f-VNTR short alleles with adult ADHD (aADHD). Association was restricted to females, as was the case in the discovery sample. Subgroup analysis on the single allele level suggested that the 21-repeat allele caused the association. Regarding subgroups, we found that NOS1 was associated with the hyperactive/impulsive ADHD subtype, but not to pure inattention. In terms of comorbidity, major depression, anxiety disorders, cluster C personality disorders and migraine were associated with short repeats, in particular the 21-repeat allele. Also, short allele carriers had significantly lower IQ. Finally, we again demonstrated an influence of the repeat on gene expression in human post-mortem brain samples. These data validate the role of NOS-I in hyperactive/impulsive phenotypes and call for further studies into the neurobiological underpinnings of this association. © 2015 Wiley Periodicals, Inc.

17.
Psychiatry Res ; 225(3): 309-14, 2015 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-25592977

RESUMO

Brain-derived neurotrophic factor (BDNF) is involved in cocaine craving in humans and drug seeking in rodents. Based on this, the aim of this study was to explore the possible role of serum BDNF in cocaine relapse in abstinent addicts. Forty cocaine dependent subjects (DSM-IV criteria) were included in an inpatient 2 weeks abstinence program. Organic and psychiatric co-morbidities were excluded. Two serum samples were collected for each subject at baseline and at after 14 abstinence days. After discharge, all cocaine addicts underwent a 22 weeks follow-up, after which they were classified into early relapsers (ER) (resumed during the first 14 days after discharge,) or late relapsers (LR) (resumed beyond 14 days after discharge). The only clinical differences between groups were the number of consumption days during the last month before detoxification. Serum BDNF levels increased significantly across the 12 days of abstinence in the LR group (p=0.02), whereas in the ER group BDNF remained unchanged. In the ER group, the change of serum BDNF during abstinence negatively correlated with the improvement in depressive symptoms (p=0.02). These results suggest that BDNF has a role in relapse to cocaine consumption in abstinent addicts, although the underlying neurobiological mechanisms remain to be clarified.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Transtornos Relacionados ao Uso de Cocaína/sangue , Cocaína , Comportamento de Procura de Droga , Síndrome de Abstinência a Substâncias/sangue , Adolescente , Adulto , Doença Crônica , Transtornos Relacionados ao Uso de Cocaína/psicologia , Depressão/sangue , Depressão/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Síndrome de Abstinência a Substâncias/psicologia , Adulto Jovem
18.
Neuropsychopharmacology ; 40(4): 915-26, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25284319

RESUMO

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high heritability. At least 30% of patients diagnosed in childhood continue to suffer from ADHD during adulthood and genetic risk factors may play an essential role in the persistence of the disorder throughout lifespan. To date, genome-wide association studies (GWAS) of ADHD have been completed in seven independent datasets, six of which were pediatric samples and one on persistent ADHD using a DNA-pooling strategy, but none of them reported genome-wide significant associations. In an attempt to unravel novel genes for the persistence of ADHD into adulthood, we conducted the first two-stage GWAS in adults with ADHD. The discovery sample included 607 ADHD cases and 584 controls. Top signals were subsequently tested for replication in three independent follow-up samples of 2104 ADHD patients and 1901 controls. None of the findings exceeded the genome-wide threshold for significance (PGC<5e-08), but we found evidence for the involvement of the FBXO33 (F-box only protein 33) gene in combined ADHD in the discovery sample (P=9.02e-07) and in the joint analysis of both stages (P=9.7e-03). Additional evidence for a FBXO33 role in ADHD was found through gene-wise and pathway enrichment analyses in our genomic study. Risk alleles were associated with lower FBXO33 expression in lymphoblastoid cell lines and with reduced frontal gray matter volume in a sample of 1300 adult subjects. Our findings point for the first time at the ubiquitination machinery as a new disease mechanism for adult ADHD and establish a rationale for searching for additional risk variants in ubiquitination-related genes.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Proteínas F-Box/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
Addict Biol ; 20(1): 22-37, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25288320

RESUMO

Frustration represents a particular aspect of the addictive process that is related to loss of control when the expected reward is not obtained. We aim to study the consequences of frustrated expected reward on gene expression in the mouse brain. For this purpose, we used an operant model of frustration using palatable food as reward combined with microarrays. Transcriptomic profiles of frontal cortex, ventral striatum and hippocampus were analysed in five groups of mice: (1) positive control receiving palatable food and the cue light as conditioned stimulus; (2) frustrated group only receiving the cue light; (3) extinction learning group that did not receive palatable food nor the light; (4) negative control that never received the reinforcer nor the light during the whole experiment; and (5) yoked that received palatable food passively. Gene expression changes produced by frustration were revealed in the frontal cortex and ventral striatum, but not in the hippocampus. Most of the changes, such as the modification of the dopamine-DARPP-32 signalling pathway, were common in both areas and estimated to have neuronal origin. Extinction learning induced transcriptional changes only in the ventral striatum, with most genes showing down-regulation and without alteration in the dopamine-DARPP-32 signalling pathway. Active palatable food-seeking behaviour induced changes in gene expression in ventral striatum mainly affecting cell communication. In conclusion, frustration behaviour-induced changes in frontal cortex and ventral striatum mainly related to dopamine-DARPP-32 signalling that could play an important role in the loss of behavioural control during the addictive processes.


Assuntos
Encéfalo/metabolismo , Condicionamento Operante/fisiologia , Frustração , RNA Mensageiro/metabolismo , Recompensa , Transcriptoma , Animais , Fosfoproteína 32 Regulada por cAMP e Dopamina/genética , Alimentos , Lobo Frontal/metabolismo , Expressão Gênica , Perfilação da Expressão Gênica , Hipocampo/metabolismo , Proteína Homeobox Nkx-2.5 , Proteínas de Homeodomínio/genética , Masculino , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição SOXD/genética , Proteína da Região Y Determinante do Sexo/genética , Transdução de Sinais , Transativadores/genética , Fatores de Transcrição/genética , Estriado Ventral/metabolismo
20.
Rev Neurol ; 58 Suppl 1: S19-24, 2014 Feb 24.
Artigo em Espanhol | MEDLINE | ID: mdl-25252662

RESUMO

The existing literature that reports findings linked with the involvement of neurotrophic factors in attention deficit hyperactivity disorder (ADHD) is reviewed. Neurotrophins, a family of neurotrophic factors, are a kind of proteins that are specific to the nervous system and play an essential role in neuron survival, differentiation and proliferation during the development of the central and peripheral nervous system. These molecules stimulate axonal growth and exert an influence on the connections with the target tissue in order to establish the synaptic connections. The study of neurotrophins in ADHD, a neurodevelopmental disorder, is of interest mainly due to the functions that these proteins perform in the central nervous system. Studies on animal, pharmacological and molecular genetic models yield evidence that relates neurotrophins with the disorder. This work reviews the results from the studies conducted to date on ADHD and neurotrophic factors, especially brain-derived neurotrophic factor (BDNF). Thus, although pharmacological studies suggest that the response to atomoxetine in adults with ADHD is not directly mediated by the effect on the BDNF, reductions in BDNF levels in the plasma of adult patients with ADHD have been reported. Further studies with broader samples and greater control of environmental factors that can regulate neurotrophin expression, such as diet, physical exercise and situations of social risk, are needed to be able to determine the role they play in the aetiology of ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Fatores de Crescimento Neural/fisiologia , Adulto , Animais , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado do Encéfalo/deficiência , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Criança , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Knockout , Fatores de Crescimento Neural/biossíntese , Fatores de Crescimento Neural/genética , Mutação Puntual , Receptor trkB/efeitos dos fármacos , Receptor trkB/genética , Sinapses/fisiologia
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