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1.
Nat Commun ; 12(1): 576, 2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33495439

RESUMO

Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10-10, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h2SNP = 0.34) when compared to ADHD without DBDs (h2SNP = 0.20), high genetic correlations between ADHD + DBDs and aggressive (rg = 0.81) and anti-social behaviors (rg = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/epidemiologia , Criança , China/epidemiologia , Estudos de Coortes , Comorbidade , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Fatores de Risco
2.
Nat Commun ; 11(1): 5272, 2020 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-33077750

RESUMO

16p11.2 and 22q11.2 Copy Number Variants (CNVs) confer high risk for Autism Spectrum Disorder (ASD), schizophrenia (SZ), and Attention-Deficit-Hyperactivity-Disorder (ADHD), but their impact on functional connectivity (FC) remains unclear. Here we report an analysis of resting-state FC using magnetic resonance imaging data from 101 CNV carriers, 755 individuals with idiopathic ASD, SZ, or ADHD and 1,072 controls. We characterize CNV FC-signatures and use them to identify dimensions contributing to complex idiopathic conditions. CNVs have large mirror effects on FC at the global and regional level. Thalamus, somatomotor, and posterior insula regions play a critical role in dysconnectivity shared across deletions, duplications, idiopathic ASD, SZ but not ADHD. Individuals with higher similarity to deletion FC-signatures exhibit worse cognitive and behavioral symptoms. Deletion similarities identified at the connectivity level could be related to the redundant associations observed genome-wide between gene expression spatial patterns and FC-signatures. Results may explain why many CNVs affect a similar range of neuropsychiatric symptoms.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/genética , Encéfalo/fisiopatologia , Esquizofrenia/genética , Adolescente , Adulto , 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 , Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno do Espectro Autista/fisiopatologia , Transtorno do Espectro Autista/psicologia , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Cognição , Estudos de Coortes , Variações do Número de Cópias de DNA , Feminino , Deleção de Genes , Duplicação Gênica , Humanos , Imagem por Ressonância Magnética , Masculino , Mutação , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/fisiopatologia , Adulto Jovem
3.
Psychiatr Danub ; 32(2): 168-175, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32796781

RESUMO

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is the most common psychiatric disorder in children. Several hypotheses have been proposed to explain its etiology. Mitochondrial dysfunction (MD) is suggested to be one of the causes of Attention Deficit Hyperactivity Disorder. The objective of the study was to evaluate the relationship between MD and ADHD by investigating mitochondrial DNA (mtDNA) levels from peripheral blood leukocytes, one of the best biomarkers of mitochondrial dysfunction. SUBJECTS AND METHODS: This study included 56 children aged 6-16 years who were diagnosed with ADHD for the first time and 56 age- and sex-matched children without ADHD. Real-time PCR was performed to determine the relative mtDNA copy number in each study participant. RESULTS: The mean mtDNA copy number of the case group was 57.623±24.827 and that of the control group was 44.204±18.926 (p=0.002). The mtDNA copy number of the case group was higher than that of the control group. Results of ROC curve analysis provided a mtDNA cutoff value of 45. CONCLUSION: Significantly higher mtDNA copy number in ADHD group may suggest mitochondrial dysfunction in the etiopathogenesis of ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Variações do Número de Cópias de DNA , DNA Mitocondrial , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/genética , Criança , Humanos , Mitocôndrias , Reação em Cadeia da Polimerase em Tempo Real
4.
Am J Psychiatry ; 177(9): 855-866, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32600152

RESUMO

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric disorder. The objective of this study was to define ADHD-associated candidate genes and their associated molecular modules and biological themes, based on the analysis of rare genetic variants. METHODS: The authors combined data from 11 published copy number variation studies in 6,176 individuals with ADHD and 25,026 control subjects and prioritized genes by applying an integrative strategy based on criteria including recurrence in individuals with ADHD, absence in control subjects, complete coverage in copy number gains, and presence in the minimal region common to overlapping copy number variants (CNVs), as well as on protein-protein interactions and information from cross-species genotype-phenotype annotation. RESULTS: The authors localized 2,241 eligible genes in the 1,532 reported CNVs, of which they classified 432 as high-priority ADHD candidate genes. The high-priority ADHD candidate genes were significantly coexpressed in the brain. A network of 66 genes was supported by ADHD-relevant phenotypes in the cross-species database. Four significantly interconnected protein modules were found among the high-priority ADHD genes. A total of 26 genes were observed across all applied bioinformatic methods. Lookup in the latest genome-wide association study for ADHD showed that among those 26 genes, POLR3C and RBFOX1 were also supported by common genetic variants. CONCLUSIONS: Integration of a stringent filtering procedure in CNV studies with suitable bioinformatics approaches can identify ADHD candidate genes at increased levels of credibility. The authors' analytic pipeline provides additional insight into the molecular mechanisms underlying ADHD and allows prioritization of genes for functional validation in validated model organisms.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Encéfalo/metabolismo , Perfilação da Expressão Gênica/métodos , RNA Polimerase III , Fatores de Processamento de RNA , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Variações do Número de Cópias de DNA/fisiologia , Bases de Dados Genéticas , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Humanos , Mapeamento de Interação de Proteínas/métodos , RNA Polimerase III/genética , RNA Polimerase III/metabolismo , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo
5.
Braz J Psychiatry ; 42(6): 630-637, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32491038

RESUMO

OBJECTIVE: Studies to reduce the heterogeneity of attention-deficit/hyperactivity disorder (ADHD) have increased interest in the concept of sluggish cognitive tempo (SCT). The aim of this study was to investigate if the prevalence of two variable-number tandem repeats (VNTRs) located within the 3'-untranslated region of the DAT1 gene and in exon 3 of the dopamine D4 receptor (DRD4) gene differ among four groups (31 subjects with SCT but no ADHD, 146 individuals with ADHD but no SCT, 67 subjects with SCT + ADHD, and 92 healthy controls). METHODS: We compared the sociodemographic profiles, neurocognitive domains, and prevalence of two VNTRs in SCT and ADHD subjects versus typically developing (TD) controls. RESULTS: The SCT without ADHD group had a higher proportion of females and lower parental educational attainment. Subjects in this group performed worse on neuropsychological tests, except for psychomotor speed and commission errors, compared to controls. However, the ADHD without SCT group performed significantly worse on all neuropsychological domains than controls. We found that 4R homozygosity for the DRD4 gene was most prevalent in the ADHD without SCT group. The SCT without ADHD group had the highest 7R allele frequency, differing significantly from the ADHD without SCT group. CONCLUSION: The 7R allele of DRD4 gene was found to be significantly more prevalent in SCT cases than in ADHD cases. No substantial neuropsychological differences were found between SCT and ADHD subjects.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Cognição , Feminino , Genótipo , Humanos , Repetições Minissatélites/genética , Receptores de Dopamina D4/genética
7.
Am J Psychiatry ; 177(6): 491-496, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32475142

RESUMO

Six articles in the June 2020 issue of the American Journal of Psychiatry address the overall construct of cognition. These articles have a broad connection to cognition, which is itself a broad concept. From the experimental psychology perspective, cognition is the set of processes associated with attending, learning, knowing, and remembering. From the clinical perspective, a number of neuropsychiatric conditions are defined by the presence of cognitive impairment, with onset ranging from childhood, such as attention deficit hyperactivity disorder and intellectual disability, to later life, such as dementia. Other conditions have notable cognitive impairments even if specific cognitive impairments are not an explicit part of their formal diagnostic criteria, including autism spectrum disorder and schizophrenia. Thus, the array of articles in this issue are related to each other and also may make important points about the role of cognition in everyday functioning and the connections between cognitive impairments in neuropsychiatric conditions and in the human population in general. Further, these articles address the neurobiological substrates that have an impact on cognition, with important implications in other domains, such as genomics. Finally, through sophisticated research methods, they clarify the results of previous studies that were affected by a variety of methodological challenges.


Assuntos
Antidepressivos/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno Autístico/epidemiologia , Benzodiazepinas/uso terapêutico , Cognição , Demência/epidemiologia , Sono , Feminino , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Fatores de Proteção , Fatores de Risco , Esquizofrenia/diagnóstico por imagem , Substância Branca/diagnóstico por imagem
8.
PLoS Med ; 17(6): e1003137, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32479557

RESUMO

BACKGROUND: Identifying causal risk factors for self-harm is essential to inform preventive interventions. Epidemiological studies have identified risk factors associated with self-harm, but these associations can be subject to confounding. By implementing genetically informed methods to better account for confounding, this study aimed to better identify plausible causal risk factors for self-harm. METHODS AND FINDINGS: Using summary statistics from 24 genome-wide association studies (GWASs) comprising 16,067 to 322,154 individuals, polygenic scores (PSs) were generated to index 24 possible individual risk factors for self-harm (i.e., mental health vulnerabilities, substance use, cognitive traits, personality traits, and physical traits) among a subset of UK Biobank participants (N = 125,925, 56.2% female) who completed an online mental health questionnaire in the period from 13 July 2016 to 27 July 2017. In total, 5,520 (4.4%) of these participants reported having self-harmed in their lifetime. In binomial regression models, PSs indexing 6 risk factors (major depressive disorder [MDD], attention deficit/hyperactivity disorder [ADHD], bipolar disorder, schizophrenia, alcohol dependence disorder, and lifetime cannabis use) predicted self-harm, with effect sizes ranging from odds ratio (OR) = 1.05 (95% CI 1.02 to 1.07, q = 0.008) for lifetime cannabis use to OR = 1.20 (95% CI 1.16 to 1.23, q = 1.33 × 10-35) for MDD. No systematic differences emerged between suicidal and non-suicidal self-harm. To further probe causal relationships, two-sample Mendelian randomisation (MR) analyses were conducted, with MDD, ADHD, and schizophrenia emerging as the most plausible causal risk factors for self-harm. The genetic liabilities for MDD and schizophrenia were associated with self-harm independently of diagnosis and medication. Main limitations include the lack of representativeness of the UK Biobank sample, that self-harm was self-reported, and the limited power of some of the included GWASs, potentially leading to possible type II error. CONCLUSIONS: In addition to confirming the role of MDD, we demonstrate that ADHD and schizophrenia likely play a role in the aetiology of self-harm using multivariate genetic designs for causal inference. Among the many individual risk factors we simultaneously considered, our findings suggest that systematic detection and treatment of core psychiatric symptoms, including psychotic and impulsivity symptoms, may be beneficial among people at risk for self-harm.


Assuntos
Comportamento Autodestrutivo/genética , Idoso , Idoso de 80 Anos ou mais , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno Bipolar/complicações , Transtorno Bipolar/genética , Bases de Dados como Assunto , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/genética , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Modelos Logísticos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Herança Multifatorial/genética , Fatores de Risco , Esquizofrenia , Comportamento Autodestrutivo/epidemiologia , Comportamento Autodestrutivo/etiologia , Transtornos Relacionados ao Uso de Substâncias/complicações , Transtornos Relacionados ao Uso de Substâncias/genética , Inquéritos e Questionários , Reino Unido/epidemiologia
10.
Epilepsia ; 61(5): 995-1007, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32469098

RESUMO

OBJECTIVE: We aimed to describe the extent of neurodevelopmental impairments and identify the genetic etiologies in a large cohort of patients with epilepsy with myoclonic atonic seizures (MAE). METHODS: We deeply phenotyped MAE patients for epilepsy features, intellectual disability, autism spectrum disorder, and attention-deficit/hyperactivity disorder using standardized neuropsychological instruments. We performed exome analysis (whole exome sequencing) filtered on epilepsy and neuropsychiatric gene sets to identify genetic etiologies. RESULTS: We analyzed 101 patients with MAE (70% male). The median age of seizure onset was 34 months (range = 6-72 months). The main seizure types were myoclonic atonic or atonic in 100%, generalized tonic-clonic in 72%, myoclonic in 69%, absence in 60%, and tonic seizures in 19% of patients. We observed intellectual disability in 62% of patients, with extremely low adaptive behavioral scores in 69%. In addition, 24% exhibited symptoms of autism and 37% exhibited attention-deficit/hyperactivity symptoms. We discovered pathogenic variants in 12 (14%) of 85 patients, including five previously published patients. These were pathogenic genetic variants in SYNGAP1 (n = 3), KIAA2022 (n = 2), and SLC6A1 (n = 2), as well as KCNA2, SCN2A, STX1B, KCNB1, and MECP2 (n = 1 each). We also identified three new candidate genes, ASH1L, CHD4, and SMARCA2 in one patient each. SIGNIFICANCE: MAE is associated with significant neurodevelopmental impairment. MAE is genetically heterogeneous, and we identified a pathogenic genetic etiology in 14% of this cohort by exome analysis. These findings suggest that MAE is a manifestation of several etiologies rather than a discrete syndromic entity.


Assuntos
Epilepsias Mioclônicas/patologia , Epilepsia Generalizada/patologia , Convulsões/patologia , Idade de Início , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/patologia , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Criança , Pré-Escolar , Eletroencefalografia , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/genética , Epilepsia Generalizada/complicações , Epilepsia Generalizada/genética , Feminino , Humanos , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Masculino , Neuroimagem , Fenótipo , Convulsões/genética , Sequenciamento Completo do Exoma
11.
PLoS Genet ; 16(5): e1008185, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32392212

RESUMO

Psychiatric disorders are highly heritable and associated with a wide variety of social adversity and physical health problems. Using genetic liability (rather than phenotypic measures of disease) as a proxy for psychiatric disease risk can be a useful alternative for research questions that would traditionally require large cohort studies with long-term follow up. Here we conducted a hypothesis-free phenome-wide association study in about 330,000 participants from the UK Biobank to examine associations of polygenic risk scores (PRS) for five psychiatric disorders (major depression (MDD), bipolar disorder (BP), schizophrenia (SCZ), attention-deficit/ hyperactivity disorder (ADHD) and autism spectrum disorder (ASD)) with 23,004 outcomes in UK Biobank, using the open-source PHESANT software package. There was evidence after multiple testing (p<2.55x10-06) for associations of PRSs with 294 outcomes, most of them attributed to associations of PRSMDD (n = 167) and PRSSCZ (n = 157) with mental health factors. Among others, we found strong evidence of association of higher PRSADHD with 1.1 months younger age at first sexual intercourse [95% confidence interval [CI]: -1.25,-0.92] and a history of physical maltreatment; PRSASD with 0.01% lower erythrocyte distribution width [95%CI: -0.013,-0.007]; PRSSCZ with 0.95 lower odds of playing computer games [95%CI:0.95,0.96]; PRSMDD with a 0.12 points higher neuroticism score [95%CI:0.111,0.135] and PRSBP with 1.03 higher odds of having a university degree [95%CI:1.02,1.03]. We were able to show that genetic liabilities for five major psychiatric disorders associate with long-term aspects of adult life, including socio-demographic factors, mental and physical health. This is evident even in individuals from the general population who do not necessarily present with a psychiatric disorder diagnosis.


Assuntos
Bancos de Espécimes Biológicos/estatística & dados numéricos , Estudo de Associação Genômica Ampla/métodos , Transtornos Mentais/epidemiologia , Transtornos Mentais/genética , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/genética , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Estudos de Coortes , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Feminino , Heterogeneidade Genética , Predisposição Genética para Doença , Humanos , Masculino , Herança Multifatorial , Fenótipo , Fatores de Risco , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Fatores Socioeconômicos , Reino Unido/epidemiologia
12.
Sci Rep ; 10(1): 8622, 2020 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-32451437

RESUMO

Attention-deficit/hyperactivity disorder (ADHD) is an impairing neurodevelopmental condition highly prevalent in current populations. Several hypotheses have been proposed to explain this paradox, mainly in the context of the Paleolithic versus Neolithic cultural shift but especially within the framework of the mismatch theory. This theory elaborates on how a particular trait once favoured in an ancient environment might become maladaptive upon environmental changes. However, given the lack of genomic data available for ADHD, these theories have not been empirically tested. We took advantage of the largest GWAS meta-analysis available for this disorder consisting of over 20,000 individuals diagnosed with ADHD and 35,000 controls, to assess the evolution of ADHD-associated alleles in European populations using archaic, ancient and modern human samples. We also included Approximate Bayesian computation coupled with deep learning analyses and singleton density scores to detect human adaptation. Our analyses indicate that ADHD-associated alleles are enriched in loss of function intolerant genes, supporting the role of selective pressures in this early-onset phenotype. Furthermore, we observed that the frequency of variants associated with ADHD has steadily decreased since Paleolithic times, particularly in Paleolithic European populations compared to samples from the Neolithic Fertile Crescent. We demonstrate this trend cannot be explained by African admixture nor Neanderthal introgression, since introgressed Neanderthal alleles are enriched in ADHD risk variants. All analyses performed support the presence of long-standing selective pressures acting against ADHD-associated alleles until recent times. Overall, our results are compatible with the mismatch theory for ADHD but suggest a much older time frame for the evolution of ADHD-associated alleles compared to previous hypotheses.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Genoma Humano , Genômica/métodos , Homem de Neandertal/genética , Alelos , Animais , Transtorno do Deficit de Atenção com Hiperatividade/história , Transtorno do Deficit de Atenção com Hiperatividade/patologia , Teorema de Bayes , Bases de Dados Genéticas , Aprendizado Profundo , Evolução Molecular , História Antiga , Humanos
13.
Am J Hum Genet ; 106(6): 830-845, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32442410

RESUMO

SOX6 belongs to a family of 20 SRY-related HMG-box-containing (SOX) genes that encode transcription factors controlling cell fate and differentiation in many developmental and adult processes. For SOX6, these processes include, but are not limited to, neurogenesis and skeletogenesis. Variants in half of the SOX genes have been shown to cause severe developmental and adult syndromes, referred to as SOXopathies. We here provide evidence that SOX6 variants also cause a SOXopathy. Using clinical and genetic data, we identify 19 individuals harboring various types of SOX6 alterations and exhibiting developmental delay and/or intellectual disability; the individuals are from 17 unrelated families. Additional, inconstant features include attention-deficit/hyperactivity disorder (ADHD), autism, mild facial dysmorphism, craniosynostosis, and multiple osteochondromas. All variants are heterozygous. Fourteen are de novo, one is inherited from a mosaic father, and four offspring from two families have a paternally inherited variant. Intragenic microdeletions, balanced structural rearrangements, frameshifts, and nonsense variants are predicted to inactivate the SOX6 variant allele. Four missense variants occur in residues and protein regions highly conserved evolutionarily. These variants are not detected in the gnomAD control cohort, and the amino acid substitutions are predicted to be damaging. Two of these variants are located in the HMG domain and abolish SOX6 transcriptional activity in vitro. No clear genotype-phenotype correlations are found. Taken together, these findings concur that SOX6 haploinsufficiency leads to a neurodevelopmental SOXopathy that often includes ADHD and abnormal skeletal and other features.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Craniossinostoses/genética , Transtornos do Neurodesenvolvimento/genética , Osteocondroma/genética , Fatores de Transcrição SOXD/genética , Transporte Ativo do Núcleo Celular , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Criança , Pré-Escolar , Simulação por Computador , Feminino , Variação Estrutural do Genoma/genética , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/diagnóstico , RNA-Seq , Fatores de Transcrição SOXD/química , Fatores de Transcrição SOXD/metabolismo , Síndrome , Transcrição Genética , Transcriptoma , Translocação Genética/genética
14.
J Clin Psychiatry ; 81(3)2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32459403

RESUMO

In observational studies, significant associations have often been identified between antidepressant drug prescription during pregnancy, on the one hand, and autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), on the other. Interpreting these associations is problematic because they are based on analyses that could not adjust for inadequately measured, unmeasured, and unknown confounds. Recent clinical data suggest that a genetic relationship exists between depression and neurodevelopmental disorders. A very recent study identified many genetic loci that were common to depression, ASD, and ADHD. These findings suggest the possibility that depression in a pregnant woman may predispose to neurodevelopmental disorders in offspring through shared genes and not through antidepressant use during pregnancy. Previous studies that significantly associated gestational exposure to antidepressants with adverse pregnancy outcomes could not adjust for genetic factors because they were unknown confounds at the time. Now that common risk loci have been identified, at least some of the unknown (genetic) confounds are no longer unknown; however, unless specifically examined in prospective studies, they will remain as unmeasured confounds that will continue to compromise the interpretation of study results. The possibility of confounding by inadequately measured, unmeasured, and unknown risk factors must therefore be considered before indicting antidepressant use during pregnancy in neurodevelopmental risks. In this context, the importance of genetic factors as unmeasured and unknown confounds must be acknowledged.


Assuntos
Antidepressivos/efeitos adversos , Transtorno Depressivo/complicações , Transtornos do Neurodesenvolvimento/genética , Complicações na Gravidez/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/genética , Antidepressivos/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/genética , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/genética , Feminino , Loci Gênicos , Predisposição Genética para Doença/genética , Humanos , Transtornos do Neurodesenvolvimento/induzido quimicamente , Gravidez , Complicações na Gravidez/psicologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente
15.
Nervenarzt ; 91(7): 575-582, 2020 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-32266439

RESUMO

All large population-based administrative studies currently indicate a significant comorbidity of adult attention deficit hyperactivity disorder (ADHD) with addictive, anxiety and in particular affective disorders. In these investigations the risk for one of these comorbid disorders increased with increasing age of the ADHD patients. The most recent genome-wide association and correlation studies also revealed indications for joint genetic risk factors of ADHD with, in particular unipolar depression, bipolar disorder, autism spectrum disorders, Tourette's syndrome and to a lesser extent schizophrenia. The only psychiatric disorder that was negatively correlated with ADHD was anorexia nervosa. Additionally, cannabis and cocaine use were significantly positively genetically correlated with ADHD. Furthermore, an increased occurrence of some specific somatic diseases could be found in patients with adult ADHD. In particular, obesity, migraine, sleep disorders, asthma and celiac disease showed a significantly positive association with ADHD in several studies. No association was found between ADHD and cardiovascular disease. Here as well there are initial indications of joint genetic risk variants; however, data are still sparse and additional studies are needed before valid conclusions can be drawn. To some extent these associated somatic diseases might be differential diagnoses rather than true comorbidities, for example, obstructive sleep apnea syndrome (OSAS) can lead to ADHD-like symptoms that disappear when the OSAS is sufficiently treated. Therefore, it is important to keep the co-occurrence of psychiatric and somatic disorders in mind during the diagnostics and treatment of adult ADHD patients to improve their general health and quality of life.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estudo de Associação Genômica Ampla , Adulto , Transtornos de Ansiedade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Comorbidade , Humanos , Qualidade de Vida
16.
Science ; 367(6484)2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32193296

RESUMO

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.


Assuntos
Córtex Cerebral/anatomia & histologia , Variação Genética , Transtorno do Deficit de Atenção com Hiperatividade/genética , Mapeamento Encefálico , Cognição , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Imagem por Ressonância Magnética , Tamanho do Órgão/genética , Doença de Parkinson/genética
18.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(2): 152-157, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32051083

RESUMO

OBJECTIVE: To study the association of microRNA expression before and after drug therapy with clinical symptoms in children with attention deficit hyperactivity disorder (ADHD). METHODS: A total of 80 previously untreated children with ADHD who were diagnosed from May 2017 to October 2018 were enrolled. The children who were willing to receive drug therapy were randomly divided into concerta-treated group with 31 children and strattera-treated group with 33 children. The children who were unwilling to receive treatment were enrolled as the untreated group with 16 children. A total of 60 children who underwent physical examination during the same period of time were enrolled as the healthy control group. SNAP-V score was determined at initial diagnosis and 3 and 6 months of follow-up. Serum samples were collected from the children with ADHD and the healthy control group. Quantitative real-time PCR was used to measure the relative expression of miR-4566-3p and miR-7641. RESULTS: The repeated measures analysis of variance showed that the SNAP-V score of attention deficit symptoms were different among the two treatment groups and the untreated group at the first visit and 3 months and 6 months after treatment (P<0.05). There were significant differences in the relative expression of the two miRNAs among the two treatment groups and the healthy control group at the first visit and 3 months and 6 months after treatment (P<0.05). The SNAP-V score of attention deficit symptoms and the relative expression of the two miRNAs were different in different time points in the subjects (P<0.05). There were interactions between grouping and time factors in the SNAP-V score of attention deficit symptoms and the relative expression of the two miRNAs (P<0.05). The SNAP-V score of hyperactive impulsive symptoms was different in different time points in the two treatment groups and the untreated group (P<0.05), but the significant difference in the score was not observed between two treatment groups and the untreated group (P>0.05), and there was no interaction between the time factor and the grouping factor (P>0.05). The SNAP-V score of attention deficit symptoms was negatively correlated with the relative expression of miRNA-4655-3p and miRNA-7641 (r=-0.314, -0.495 respectively; P<0.05) in ADHD children after drug treatment. CONCLUSIONS: Drug therapy can significantly improve the clinical symptoms of children with ADHD. The expression of miR-4655-3p and miR-7641 in serum can be used as biomarkers for the diagnosis and outcome evaluation of ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , MicroRNAs/genética , Cloridrato de Atomoxetina , Transtorno do Deficit de Atenção com Hiperatividade/genética , Criança , Humanos
19.
Gac Med Mex ; 156(1): 60-66, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32026885

RESUMO

Fragile X syndrome is the monogenetic condition that produces more cases of autism and intellectual disability. The repetition of CGG triplets (> 200) and their methylation entail the silencing of the FMR1 gene. The FMRP protein (product of the FMR1 gene) interacts with ribosomes by controlling the translation of specific messengers, and its loss causes alterations in synaptic connectivity. Screening for fragile X syndrome is performed by polymerase chain reaction. Current recommendation of the American Academy of Pediatrics is to test individuals with intellectual disability, global developmental retardation or with a family history of presence of the mutation or premutation. Hispanic countries such as Colombia, Chile and Spain report high prevalence of fragile X syndrome and have created fragile X national associations or corporations that seek to bring patients closer to available diagnostic and treatment networks.


Assuntos
Transtorno Autístico/genética , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Deficiência Intelectual/genética , Transtorno do Deficit de Atenção com Hiperatividade/genética , Lista de Checagem , Pré-Escolar , Feminino , Proteína do X Frágil de Retardo Mental/metabolismo , Síndrome do Cromossomo X Frágil/complicações , Síndrome do Cromossomo X Frágil/diagnóstico , Síndrome do Cromossomo X Frágil/terapia , Inativação Gênica , Testes Genéticos , Humanos , Masculino , Mutação , Linhagem , Fenótipo , Ribossomos/metabolismo , Fatores Sexuais , Transmissão Sináptica
20.
Am J Psychiatry ; 177(6): 526-536, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32046534

RESUMO

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable neuropsychiatric disorder. ADHD often co-occurs with intellectual disability, and shared overlapping genetics have been suggested. The aim of this study was to identify novel ADHD genes by investigating whether genes carrying rare mutations linked to intellectual disability contribute to ADHD risk through common genetic variants. Validation and characterization of candidates were performed using Drosophila melanogaster. METHODS: Common genetic variants in a diagnostic gene panel of 396 autosomal intellectual disability genes were tested for association with ADHD risk through gene set and gene-wide analyses, using ADHD meta-analytic data from the Psychiatric Genomics Consortium for discovery (N=19,210) and ADHD data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research for replication (N=37,076). The significant genes were functionally validated and characterized in Drosophila by assessing locomotor activity and sleep upon knockdown of those genes in brain circuits. RESULTS: The intellectual disability gene set was significantly associated with ADHD risk in the discovery and replication data sets. The three genes most consistently associated were MEF2C, ST3GAL3, and TRAPPC9. Performing functional characterization of the two evolutionarily conserved genes in Drosophila melanogaster, the authors found that their knockdown in dopaminergic (dMEF2) and circadian neurons (dTRAPPC9) resulted in increased locomotor activity and reduced sleep, concordant with the human phenotype. CONCLUSIONS: This study reveals that a large set of intellectual disability-related genes contribute to ADHD risk through effects of common alleles. Utilizing this continuity, the authors identified TRAPPC9, MEF2C, and ST3GAL3 as novel ADHD candidate genes. Characterization in Drosophila suggests that TRAPPC9 and MEF2C contribute to ADHD-related behavior through distinct neural substrates.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Locomoção/genética , Fatores de Regulação Miogênica/genética , Sialiltransferases/genética , Adulto , Idoso , Animais , Ritmo Circadiano , Neurônios Dopaminérgicos/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Humanos , Deficiência Intelectual/genética , Fatores de Transcrição MEF2/genética , Masculino , Pessoa de Meia-Idade , Neurônios/metabolismo , Sono/genética
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