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1.
Nat Commun ; 11(1): 4796, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963231

RESUMO

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/ß-catenin, TGF-ß and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.


Assuntos
Envelhecimento/genética , Encéfalo , Estudo de Associação Genômica Ampla , Transtornos Mentais/genética , Doenças Neurodegenerativas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estruturas Cromossômicas , Cognição , Feminino , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único
2.
Psychiatr Danub ; 32(Suppl 1): 158-163, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32890382

RESUMO

BACKGROUND: Some behaviors or psychiatric conditions seem to be inherited from parents or explain by family environment. We hypothesized interactions between epigenetic processes, inflammatory response and gut microbiota with family surroundings or environmental characteristics. SUBJECTS AND METHODS: We searched in literature interactions between epigenetic processes and psychiatric disorders with a special interest for environmental factors such as traumatic or stress events, family relationships and also gut microbiota. We searched on Pubmed, PsycINFO, PsycARTICLES and Sciencedirect articles with the keywords psychiatric disorders, epigenome, microbiome and family relationships. RESULTS: Some gene polymorphisms interact with negative environment and lead to psychiatric disorders. Negative environment is correlated with different epigenetic modifications in genes implicated in mental health. Gut microbiota diversity affect host epigenetic. Animal studies showed evidences for a transgenerational transmission of epigenetic characteristics. CONCLUSIONS: Our findings support the hypothesis that epigenetic mediate gene-environment interactions and psychiatric disorders. Several environmental characteristics such as traumatic life events, family adversity, psychological stress or internal environment such as gut microbiota diversity and diet showed an impact on epigenetic. These epigenetic modifications are also correlated with neurophysiological, inflammatory or hypothalamic-pituitary-adrenal axis dysregulations.


Assuntos
Epigênese Genética , Microbioma Gastrointestinal , Transtornos Mentais , Animais , Sistema Hipotálamo-Hipofisário , Transtornos Mentais/genética , Transtornos Mentais/microbiologia , Sistema Hipófise-Suprarrenal
3.
PLoS One ; 15(8): e0237001, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790782

RESUMO

Why people differ in their susceptibility to external events is essential to our understanding of personality, human development, and mental disorders. Genes explain a substantial portion of these differences. Specifically, genes influencing the serotonin system are hypothesized to be differential susceptibility factors, determining a person's reactivity to both positive and negative environments. We tested whether genetic variation in the serotonin transporter (5-HTTLPR) is a differential susceptibility factor for daily events. Participants (N = 326, 77% female, mean age = 25, range = 17-36) completed smartphone questionnaires four times a day over four to five days, measuring stressors, uplifts, positive and negative affect. Affect was predicted from environment valence in the previous hour on a within-person level using three-level autoregressive linear mixed models. The 5-HTTLPR fulfilled all criteria of a differential susceptibility factor: Positive affect in carriers of the short allele (S) was less reactive to both uplifts and stressors, compared to homozygous carriers of the long allele (L/L). This pattern might reflect relative affective inflexibility in S-allele carriers. Our study provides insight into the serotonin system's general role in susceptibility and highlights the need to assess the whole spectrum of naturalistic experiences.


Assuntos
Predisposição Genética para Doença , Acontecimentos que Mudam a Vida , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Estresse Psicológico/genética , Adolescente , Adulto , Afeto , Alelos , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Transtornos Mentais/genética , Pessoa de Meia-Idade , Modelos Genéticos , Modelos Psicológicos , Inquéritos e Questionários , Adulto Jovem
4.
Nat Commun ; 11(1): 3143, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32561719

RESUMO

Topoisomerase 3ß (Top3ß) is the only dual-activity topoisomerase in animals that can change topology for both DNA and RNA, and facilitate transcription on DNA and translation on mRNAs. Top3ß mutations have been linked to schizophrenia, autism, epilepsy, and cognitive impairment. Here we show that Top3ß knockout mice exhibit behavioural phenotypes related to psychiatric disorders and cognitive impairment. The mice also display impairments in hippocampal neurogenesis and synaptic plasticity. Notably, the brains of the mutant mice exhibit impaired global neuronal activity-dependent transcription in response to fear conditioning stress, and the affected genes include many with known neuronal functions. Our data suggest that Top3ß is essential for normal brain function, and that defective neuronal activity-dependent transcription may be a mechanism by which Top3ß deletion causes cognitive impairment and psychiatric disorders.


Assuntos
Disfunção Cognitiva/genética , DNA Topoisomerases Tipo I/genética , Transtornos Mentais/genética , Neurogênese/genética , Plasticidade Neuronal/genética , Animais , Técnicas de Observação do Comportamento , Comportamento Animal , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Feminino , Hipocampo/citologia , Hipocampo/diagnóstico por imagem , Hipocampo/crescimento & desenvolvimento , Hipocampo/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Transtornos Mentais/diagnóstico , Transtornos Mentais/patologia , Camundongos , Camundongos Knockout , Neurônios/patologia , Técnicas Estereotáxicas , Potenciais Sinápticos/genética , Transcrição Genética/fisiologia
5.
Orv Hetil ; 161(20): 821-828, 2020 05 01.
Artigo em Húngaro | MEDLINE | ID: mdl-32364361

RESUMO

The protein product of the nuclear-encoded POLG gene plays a key role in the maintenance of mitochondrial DNA replication, and its failure causes multi-system diseases with varying severity. The clinical spectrum is extremely wide, and the most common symptoms include ptosis, myoclonus, epilepsy, myopathy, sensory ataxia, parkinsonism, cognitive decline and infertility. Now, it is known that mitochondrial dysfunction in Parkinson's disease plays a key role in the loss of dopaminergic neurons in the substantia nigra. Therefore, changes in the POLG gene may influence the development of various hereditary neurodegenerative diseases, including monogenic parkinsonism. However, only limited information is available on the relationship between Parkinson's disease and POLG gene and until now, there are no available data about the Hungarian population. In our study, we performed a next-generation sequencing study of 67 Hungarian patients with parkinsonism and analyzed the potentially damaging alterations in the POLG gene. 3 patients have been identified with a potential pathogen variant. In this study, we would like to call attention to the fact that during the differential diagnosis of parkinsonism, the possible involvement of POLG gene should be kept in mind. Especially in the presence of additional symptoms, such as ophthalmoparesis, non-vascular white matter lesions, psychiatric comorbidity, and relatively early age of onset, the POLG gene should be taken into consideration. Based on previous data from the literature and our own experience, we have summarized a possible diagnostic approach for POLG-associated parkinsonism. Orv Hetil. 2020; 161(20): 821-828.


Assuntos
Polimerase do DNA Mitocondrial/genética , Predisposição Genética para Doença , Doença de Parkinson/genética , Comorbidade , DNA Mitocondrial/metabolismo , Humanos , Hungria , Transtornos Mentais/genética , Mutação , Oftalmoplegia/genética , Doença de Parkinson/diagnóstico , Transtornos Parkinsonianos/genética
8.
Adv Exp Med Biol ; 1195: 237-247, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468482

RESUMO

MicroRNAs (miRNAs) are small non-coding RNA molecules of about 20-22 nucleotides. After their posttranscriptional maturation, miRNAs are loaded into the ribonucleoprotein complex RISC and modulate gene expression by binding to the 3' untranslated region of their target mRNAs through base-pairing, which in turn triggers mRNA degradation or translational inhibition. There is mounting evidence that miRNAs regulate various biological processes, including cell proliferation, differentiation, and apoptosis. Several studies have shown that miRNAs play an important role in neurogenesis and brain development.This review discusses recent progress on understanding the implication of precisely regulated miRNA expression in normal brain development and function. In addition, it reports known cases of dysregulation of miRNA expression and function implicated in the pathogenesis of neurodevelopmental disorders, craniofacial dysmorphic syndromes, neurodegenerative diseases, and psychiatric disorders. Current knowledge regarding the role of miRNAs in the brain in conjunction with the complex interplay between genetic and epigenetic factors are discussed.


Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiologia , MicroRNAs/metabolismo , Regiões 3' não Traduzidas/genética , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/metabolismo , Humanos , Transtornos Mentais/genética , Transtornos Mentais/metabolismo , MicroRNAs/genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Neurogênese/genética
9.
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
11.
Adv Exp Med Biol ; 1194: 455, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468561

RESUMO

The majority of risk genetic variants for common and complex neuropsychiatric traits lie within noncoding regions. Previous efforts have linked risk variants to specific genes by leveraging transcriptome data and expression quantitative trait loci. Most recently, the generation of large-scale epigenome data and the availability of epigenome quantitative trait loci provide a powerful discovery tool for assigning a functional role to the genetic variation in neuropsychiatric traits. In this talk, we will focus on advances in integration of epigenome datasets with the risk of common and complex neuropsychiatric traits.


Assuntos
Análise de Dados , Epigenoma , Transtornos Mentais , Doenças do Sistema Nervoso , Locos de Características Quantitativas , Epigenoma/genética , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Transtornos Mentais/diagnóstico , Transtornos Mentais/genética , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/genética
14.
Nat Neurosci ; 23(4): 475-480, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32231337

RESUMO

Over the last decade, genome-wide association studies of psychiatric disorders have identified numerous significant loci. Whereas these studies initially depended on cohorts ascertained for specific disorders, there has been a gradual shift in the ascertainment strategy toward population-based cohorts for which both genotype and heterogeneous phenotypic information are available. One of the advantages of population-based cohorts is that, in addition to clinical diagnoses and various proxies for diagnoses ('minimal phenotyping'), many of them also provide non-clinical phenotypes, including putative endophenotypes, that can be used to study domains of normal function in addition to, or instead of, clinical diagnoses. By studying endophenotypes it is possible to both dissect psychiatric disorders ('splitting') and to combine multiple phenotypes ('clumping'), which can either reinforce or challenge traditional diagnostic categories. Such endophenotypes may also permit a deeper exploration of the neurobiology of psychiatric disorders. A coordinated effort to fully exploit the potential of endophenotypes is overdue.


Assuntos
Endofenótipos , Predisposição Genética para Doença , Genótipo , Transtornos Mentais/genética , Fenótipo , Estudo de Associação Genômica Ampla , Humanos
15.
Nat Commun ; 11(1): 1770, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317632

RESUMO

Leisure sedentary behaviours are associated with increased risk of cardiovascular disease, but whether this relationship is causal is unknown. The aim of this study is to identify genetic determinants associated with leisure sedentary behaviours and to estimate the potential causal effect on coronary artery disease (CAD). Genome wide association analyses of leisure television watching, leisure computer use and driving behaviour in the UK Biobank identify 145, 36 and 4 genetic loci (P < 1×10-8), respectively. High genetic correlations are observed between sedentary behaviours and neurological traits, including education and body mass index (BMI). Two-sample Mendelian randomization (MR) analysis estimates a causal effect between 1.5 hour increase in television watching and CAD (OR 1.44, 95%CI 1.25-1.66, P = 5.63 × 10-07), that is partially independent of education and BMI in multivariable MR analyses. This study finds independent observational and genetic support for the hypothesis that increased sedentary behaviour by leisure television watching is a risk factor for CAD.


Assuntos
Doença da Artéria Coronariana , Transtornos Mentais/genética , Comportamento Sedentário , Adulto , Idoso , Índice de Massa Corporal , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/etiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Transtornos Mentais/complicações , Pessoa de Meia-Idade , Fatores de Risco , Reino Unido/epidemiologia
17.
PLoS One ; 15(3): e0229730, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32119710

RESUMO

The tryptophan hydroxylase 2 (TPH2) enzyme catalyzes the first step of serotonin biosynthesis. Serotonin is known for its role in several homeostatic systems related to sleep, mood, and food intake. As the reaction catalyzed by TPH2 is the rate-limiting step of serotonin biosynthesis, mutations in TPH2 have been associated with several psychiatric disorders (PD). This work undertakes an in silico analysis of the effects of genetic mutations in the human TPH2 protein. Ten algorithms were used to predict the functional and stability effects of the TPH2 mutations. ConSurf was used to estimate the evolutionary conservation of TPH2 amino acids. GROMACS was used to perform molecular dynamics (MD) simulations of TPH2 WT and P260S, R303W, and R441H, which had already been associated with the development of PD. Forty-six TPH2 variants were compiled from the literature. Among the analyzed variants, those occurring at the catalytic domain were shown to be more damaging to protein structure and function. The ConSurf analysis indicated that the mutations affecting the catalytic domain were also more conserved throughout evolution. The variants S364K and S383F were predicted to be deleterious by all the functional algorithms used and occurred at conserved positions, suggesting that they might be deleterious. The MD analyses indicate that the mutations P206S, R303W, and R441H affect TPH2 flexibility and essential mobility at the catalytic and oligomerization domains. The variants P206S, R303W, and R441H also exhibited alterations in dimer binding affinity and stability throughout the simulations. Thus, these mutations may impair TPH2 functional interactions and, consequently, its function, leading to the development of PD. Furthermore, we developed a database, SNPMOL (http://www.snpmol.org/), containing the results presented in this paper. Understanding the effects of TPH2 mutations on protein structure and function may lead to improvements in existing treatments for PD and facilitate the design of further experiments.


Assuntos
Simulação por Computador , Transtornos Mentais/enzimologia , Transtornos Mentais/genética , Mutação/genética , Triptofano Hidroxilase/química , Triptofano Hidroxilase/genética , Sequência Conservada , Cristalografia por Raios X , Estabilidade Enzimática , Evolução Molecular , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Simulação de Dinâmica Molecular , Análise de Componente Principal , Estrutura Secundária de Proteína
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