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1.
Medicine (Baltimore) ; 99(35): e21989, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871949

RESUMO

BACKGROUND: Bipolar disorder (BD), a common kind of mood disorder with frequent recurrence, high rates of additional comorbid conditions and poor compliance, has an unclear pathogenesis. The Gene Expression Omnibus (GEO) database is a gene expression database created and maintained by the National Center for Biotechnology Information. Researchers can download expression data online for bioinformatics analysis, especially for cancer research. However, there is little research on the use of such bioinformatics analysis methodologies for mental illness by downloading differential expression data from the GEO database. METHODS: Publicly available data were downloaded from the GEO database (GSE12649, GSE5388 and GSE5389), and differentially expressed genes (DEGs) were extracted by using the online tool GEO2R. A Venn diagram was used to screen out common DEGs between postmortem brain tissues and normal tissues. Functional annotation and pathway enrichment analysis of DEGs were performed by using Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses, respectively. Furthermore, a protein-protein interaction network was constructed to identify hub genes. RESULTS: A total of 289 DEGs were found, among which 5 of 10 hub genes [HSP90AA1, HSP90AB 1, UBE2N, UBE3A, and CUL1] were identified as susceptibility genes whose expression was downregulated. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that variations in these 5 hub genes were obviously enriched in protein folding, protein polyubiquitination, apoptotic process, protein binding, the ubiquitin-mediated proteolysis pathway, and protein processing in the endoplasmic reticulum pathway. These findings strongly suggested that HSP90AA1, UBE3A, and CUL 1, which had large areas under the curve in receiver operator curves (P < .05), were potential diagnostic markers for BD. CONCLUSION: Although there are 3 hub genes [HSP90AA1, UBE3A, and CUL 1] that are tightly correlated with the occurrence of BD, mainly based on routine bioinformatics methods for cancer-related disease, the feasibility of applying this single GEO bioinformatics approach for mental illness is questionable, given the significant differences between mental illness and cancer-related diseases.


Assuntos
Transtorno Bipolar/genética , Proteínas Culina/genética , Mineração de Dados/métodos , Proteínas de Choque Térmico HSP90/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Mapas de Interação de Proteínas , Adulto Jovem
2.
PLoS Genet ; 16(9): e1009015, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32956347

RESUMO

Evidence from both GWAS and clinical observation has suggested that certain psychiatric, metabolic, and autoimmune diseases are heterogeneous, comprising multiple subtypes with distinct genomic etiologies and Polygenic Risk Scores (PRS). However, the presence of subtypes within many phenotypes is frequently unknown. We present CLiP (Correlated Liability Predictors), a method to detect heterogeneity in single GWAS cohorts. CLiP calculates a weighted sum of correlations between SNPs contributing to a PRS on the case/control liability scale. We demonstrate mathematically and through simulation that among i.i.d. homogeneous cases generated by a liability threshold model, significant anti-correlations are expected between otherwise independent predictors due to ascertainment on the hidden liability score. In the presence of heterogeneity from distinct etiologies, confounding by covariates, or mislabeling, these correlation patterns are altered predictably. We further extend our method to two additional association study designs: CLiP-X for quantitative predictors in applications such as transcriptome-wide association, and CLiP-Y for quantitative phenotypes, where there is no clear distinction between cases and controls. Through simulations, we demonstrate that CLiP and its extensions reliably distinguish between homogeneous and heterogeneous cohorts when the PRS explains as low as 3% of variance on the liability scale and cohorts comprise 50, 000 - 100, 000 samples, an increasingly practical size for modern GWAS. We apply CLiP to heterogeneity detection in schizophrenia cohorts totaling > 50, 000 cases and controls collected by the Psychiatric Genomics Consortium. We observe significant heterogeneity in mega-analysis of the combined PGC data (p-value 8.54 × 0-4), as well as in individual cohorts meta-analyzed using Fisher's method (p-value 0.03), based on significantly associated variants. We also apply CLiP-Y to detect heterogeneity in neuroticism in over 10, 000 individuals from the UK Biobank and detect heterogeneity with a p-value of 1.68 × 10-9. Scores were not significantly reduced when partitioning by known subclusters ("Depression" and "Worry"), suggesting that these factors are not the primary source of observed heterogeneity.


Assuntos
Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Herança Multifatorial/genética , Algoritmos , Transtorno Bipolar/genética , Estudos de Casos e Controles , Bases de Dados Genéticas , Transtorno Depressivo Maior/genética , Feminino , Heterogeneidade Genética , Predisposição Genética para Doença/genética , Humanos , Masculino , Modelos Teóricos , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Esquizofrenia/genética
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(9): 991-996, 2020 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-32820514

RESUMO

OBJECTIVE: To explore the correlation between altered levels of neurotransmitters in the frontal lobe and hippocampus and behavioral abnormalities in a Clockdelta19 variant mice modeling bipolar disorder manic disorder. METHODS: Open field test and Elevated plus-maze test were carried out on the Clockdelta19 mutant and wild-type control groups. The frontal lobe and hippocampus of Clockdelta19 mutant mice and controls were dissected, and neurotransmitters in tissue extracts were analyzed by high-performance liquid chromatography and mass spectrometry. The concentration of neurotransmitters and behavioral indicators were assessed by t test and Pearson correlation analysis using SPSS 22.0. RESULTS: The Clockdelta19 mutant mice showed a significant increase in activity, albeit with no difference in the level of anxiety from the wild-type controls, which suggested that the Clockdelta19 mutant mice can be used as a model for manic attack of bipolar disorder. Altered neurotransmitter levels were detected in the frontal and hippocampal regions, including elevated histamine in the left hippocampus, reduced histamine in the right hippocampus, reduced gamma-aminobutyric acid (GABA) in bilateral hippocampus, elevated dihydroxyphenylalanine (DOPA) in the left frontal lobe and reduced DOPA in the right hippocampus, and decreased glutamine in bilateral frontal lobes. The reduced glutamine in the left frontal lobe and GABA in the right hippocampus correlated with the increased activity of Clockdelta19 mutant mice. CONCLUSION: Clockdelta19 mutant mice showed abnormal behavior with increased activity. Reduced glutamine in the left frontal lobe and GABA in the right hippocampus were correlated with increased activity.


Assuntos
Comportamento Animal , Transtorno Bipolar , Proteínas CLOCK/genética , Neurotransmissores/análise , Animais , Transtorno Bipolar/genética , Lobo Frontal/química , Hipocampo/química , Humanos , Camundongos , Atividade Motora
4.
Am J Psychiatry ; 177(10): 936-943, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32660297

RESUMO

OBJECTIVE: The authors investigated the associations between polygenic liability and progression to bipolar disorder or psychotic disorders among individuals diagnosed with unipolar depression in early life. METHODS: A cohort comprising 16,949 individuals (69% female, 10-35 years old at the first depression diagnosis) from the iPSYCH Danish case-cohort study (iPSYCH2012) who were diagnosed with depression in Danish psychiatric hospitals from 1994 to 2016 was examined. Polygenic risk scores (PRSs) for major depression, bipolar disorder, and schizophrenia were generated using the most recent results from the Psychiatric Genomics Consortium. Hazard ratios for each disorder-specific PRS were estimated using Cox regressions with adjustment for the other two PRSs. Absolute risk of progression was estimated using the cumulative hazard. RESULTS: Patients were followed for up to 21 years (median=7 years, interquartile range, 5-10 years). The absolute risks of progression to bipolar disorder and psychotic disorders were 7.3% and 13.8%, respectively. After mutual adjustment for the other PRSs, only the PRS for bipolar disorder predicted progression to bipolar disorder (adjusted hazard ratio for a one-standard-deviation increase in PRS=1.11, 95% CI=1.03, 1.21), and only the PRS for schizophrenia predicted progression to psychotic disorders (adjusted hazard ratio=1.10, 95% CI=1.04, 1.16). After adjusting for PRSs, parental history still strongly predicted progression to bipolar disorder (adjusted hazard ratio=5.02, 95% CI=3.53, 7.14) and psychotic disorders (adjusted hazard ratio=1.63, 95% CI=1.30, 2.06). CONCLUSIONS: PRSs for bipolar disorder and schizophrenia are associated with risk for progression to bipolar disorder or psychotic disorders, respectively, among individuals diagnosed with depression; however, the effects are small compared with parental history, particularly for bipolar disorder.


Assuntos
Transtorno Bipolar/genética , Transtorno Depressivo/genética , Herança Multifatorial/genética , Transtornos Psicóticos/genética , Adolescente , Adulto , Criança , Dinamarca , Progressão da Doença , Feminino , Técnicas de Genotipagem , Humanos , Masculino , Fatores de Risco , Esquizofrenia/genética , Adulto Jovem
6.
BMC Psychiatry ; 20(1): 349, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620087

RESUMO

BACKGROUND: Megalencephalic leukoencephalopathy with subcortical cysts (MLC), or Van der Knaap disease, is a rare spongiform leukodystrophy that is characterized by macrocephaly, progressive motor dysfunction, and mild mental retardation. It is very rare for mental illness such as psychotic disorders, affective disorders and anxiety disorders to occur in MLC. CASE PRESENTATION: A 17-year-old boy was admitted to our hospital after he developed symptoms of depressive state with catatonia after being diagnosed as having MLC with confirmed MLC1 mutation. His catatonic symptoms were improved with administration of olanzapine and sertraline and he was discharged after 4 months. Several months later, he became hypomanic. He was diagnosed with bipolar II disorder. Mood swings were controlled with the administration of carbamazepine. CONCLUSIONS: This case is the first report of bipolar disorder during the clinical course of MLC. This case indicate the possibility that MLC influences the development of bipolar disorder in MLC, however, further studies involving more patients are required to clarify this.


Assuntos
Transtorno Bipolar/diagnóstico , Encéfalo/diagnóstico por imagem , Catatonia/complicações , Cistos , Depressão/complicações , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central , Adolescente , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Catatonia/diagnóstico , Cistos/diagnóstico , Cistos/genética , Depressão/diagnóstico , Feminino , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Humanos , Imagem por Ressonância Magnética , Megalencefalia
7.
Sci Rep ; 10(1): 12239, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32699220

RESUMO

Lithium (Li) is the cornerstone maintenance treatment for bipolar disorders (BD), but response rates are highly variable. To date, no clinical or biological marker is available to reliably define eligibility criteria for a maintenance treatment with Li. We examined whether the prophylactic response to Li (assessed retrospectively) is associated with distinct blood DNA methylation profiles. Bisulfite-treated total blood DNA samples from individuals with BD type 1 (15 excellent-responders (LiERs) versus 11 non-responders (LiNRs)) were used for targeted enrichment of CpG rich genomic regions followed by high-resolution next-generation sequencing to identify differentially methylated regions (DMRs). After controlling for potential confounders we identified 111 DMRs that significantly differ between LiERs and LiNRs with a significant enrichment in neuronal cell components. Logistic regression and receiver operating curves identified a combination of 7 DMRs with a good discriminatory power for response to Li (Area Under the Curve 0.806). Annotated genes associated with these DMRs include Eukaryotic Translation Initiation Factor 2B Subunit Epsilon (EIF2B5), Von Willebrand Factor A Domain Containing 5B2 (VWA5B2), Ral GTPase Activating Protein Catalytic Alpha Subunit 1 (RALGAPA1). Although preliminary and deserving replication, these results suggest that biomarkers of response to Li may be identified through peripheral epigenetic measures.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Lítio/uso terapêutico , Biomarcadores/metabolismo , Ilhas de CpG/efeitos dos fármacos , Ilhas de CpG/genética , DNA/genética , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
8.
Rev. neurol. (Ed. impr.) ; 71(2): 61-68, 16 jul., 2020. graf
Artigo em Espanhol | IBECS | ID: ibc-195447

RESUMO

INTRODUCCIÓN: Se discute si la consanguinidad es un factor de riesgo para sufrir trastorno bipolar o esquizofrenia. Los árboles genealógicos de las casas reales son una oportunidad para estudiarlo. Felipe V posiblemente sufrió un trastorno mental grave, como también su hijo Fernando VI. Sin embargo, Carlos III, también hijo de Felipe V, pero fruto de otro matrimonio, aparentemente no. Se mantiene la hipótesis de que la consanguinidad podría haber sido un factor de riesgo para ello. SUJETOS Y MÉTODOS: Se analizan las biografías de estos tres reyes para detectar si sufrieron algún trastorno mental de acuerdo con el DSM-5 y la CIE-11. Se estudia su coeficiente de consanguinidad mediante el programa PedPro con una base de datos de 25.776 individuos. RESULTADOS: Felipe V y Fernando VI podrían haber sido diagnosticados de trastorno bipolar, mientras que Carlos III podría haberlo sido de un leve trastorno de la personalidad. Felipe V y Fernando VI tenían un coeficiente de consanguinidad elevado (0,091109 y 0,095023, respectivamente), mientras que en Carlos III era sólo de 0,038264. El coeficiente de los dos primeros es mayor que el de los hijos de primos hermanos (0,0625). CONCLUSIONES: Felipe V y Fernando VI sufrieron un trastorno bipolar. El análisis de los árboles genéticos mediante el coeficiente de consanguinidad es una valiosa herramienta para el estudio de la heredabilidad del trastorno bipolar. La endogamia acumula alelos patógenos y el riesgo de sufrirlo. En estos sujetos, la alta consanguinidad fue un importante factor etiopatogénico de la enfermedad que sufrieron. Una elevada consanguinidad supone un factor de riesgo de sufrir trastorno bipolar


INTRODUCTION: There is an argument about inbreeding as a risk factor in the development of major mental illnesses like bipolar disorder or schizophrenia. The genealogical trees of European royal dynasties represent an opportunity to study this relationship. Felipe V was the first Bourbon king to rule in Spain, who was thought to have possibly suffered a severe mental disorder. Felipe's son Fernando VI, also had a mental disease. Nevertheless Carlos III, Felipe V's son born from a different, unrelated mother, apparently showed no trace of such disorder. We hypothesize that consanguinity or inbreeding could explain the tendency in the acquiring of severe mental disorders. SUBJECTS AND METHODS: Biographies of three Spanish Bourbon kings (Felipe V, Fernando VI and Carlos III) were analysed in order to evaluate if they were likely to have suffered from some mental disorder, according to DSM-5 and ICD-11 criteria. An inbreeding coefficient was determined with the PedPro Program. RESULTS: Felipe V and Fernando VI could have been diagnosed with bipolar disorder, whereas Carlos III could have been diagnosed with a mild personality disorder. Both Felipe V and Fernando VI had a high inbreeding coefficient (0.091109 and 0.095023, respectively), while Carlos III had a lower one (0.038264). The inbreeding coefficient of siblings of couples of first grade cousins is 0.0625. CONCLUSIONS: A high inbreeding coefficient is a risk factor in developing bipolar disorder. Felipe V and Fernando VI suffered from bipolar disorder. The analysis of genetic trees by the inbreeding coefficient is a valuable tool in the study of heredability of bipolar disorder. Endogamy accumulates pathogenic alleles and increases risk to suffer it. These kings had a high consanguinity which was an important risk factor to the illness. High consanguinity is a risk factor to suffer bipolar disorder


Assuntos
Humanos , História do Século XVIII , Consanguinidade , Transtornos Mentais/genética , Transtornos Mentais/história , Transtorno Bipolar/genética , Transtorno Bipolar/história , Timidez , Medo , Depressão
9.
Proc Natl Acad Sci U S A ; 117(26): 15028-15035, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32522875

RESUMO

To correct for a large number of hypothesis tests, most researchers rely on simple multiple testing corrections. Yet, new methodologies of selective inference could potentially improve power while retaining statistical guarantees, especially those that enable exploration of test statistics using auxiliary information (covariates) to weight hypothesis tests for association. We explore one such method, adaptive P-value thresholding (AdaPT), in the framework of genome-wide association studies (GWAS) and gene expression/coexpression studies, with particular emphasis on schizophrenia (SCZ). Selected SCZ GWAS association P values play the role of the primary data for AdaPT; single-nucleotide polymorphisms (SNPs) are selected because they are gene expression quantitative trait loci (eQTLs). This natural pairing of SNPs and genes allow us to map the following covariate values to these pairs: GWAS statistics from genetically correlated bipolar disorder, the effect size of SNP genotypes on gene expression, and gene-gene coexpression, captured by subnetwork (module) membership. In all, 24 covariates per SNP/gene pair were included in the AdaPT analysis using flexible gradient boosted trees. We demonstrate a substantial increase in power to detect SCZ associations using gene expression information from the developing human prefrontal cortex. We interpret these results in light of recent theories about the polygenic nature of SCZ. Importantly, our entire process for identifying enrichment and creating features with independent complementary data sources can be implemented in many different high-throughput settings to ultimately improve power.


Assuntos
Transtorno Bipolar/genética , Esquizofrenia/genética , Algoritmos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
10.
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
12.
BMC Bioinformatics ; 21(1): 178, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32381021

RESUMO

BACKGROUND: Heterogeneity in the definition and measurement of complex diseases in Genome-Wide Association Studies (GWAS) may lead to misdiagnoses and misclassification errors that can significantly impact discovery of disease loci. While well appreciated, almost all analyses of GWAS data consider reported disease phenotype values as is without accounting for potential misclassification. RESULTS: Here, we introduce Phenotype Latent variable Extraction of disease misdiagnosis (PheLEx), a GWAS analysis framework that learns and corrects misclassified phenotypes using structured genotype associations within a dataset. PheLEx consists of a hierarchical Bayesian latent variable model, where inference of differential misclassification is accomplished using filtered genotypes while implementing a full mixed model to account for population structure and genetic relatedness in study populations. Through simulations, we show that the PheLEx framework dramatically improves recovery of the correct disease state when considering realistic allele effect sizes compared to existing methodologies designed for Bayesian recovery of disease phenotypes. We also demonstrate the potential of PheLEx for extracting new potential loci from existing GWAS data by analyzing bipolar disorder and epilepsy phenotypes available from the UK Biobank. From the PheLEx analysis of these data, we identified new candidate disease loci not previously reported for these datasets that have value for supplemental hypothesis generation. CONCLUSION: PheLEx shows promise in reanalyzing GWAS datasets to provide supplemental candidate loci that are ignored by traditional GWAS analysis methodologies.


Assuntos
Algoritmos , Estudo de Associação Genômica Ampla , Área Sob a Curva , Teorema de Bayes , Transtorno Bipolar/genética , Simulação por Computador , Bases de Dados Genéticas , Predisposição Genética para Doença , Genótipo , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Curva ROC
13.
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
14.
Braz J Psychiatry ; 42(5): 536-551, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32267339

RESUMO

Bipolar disorder (BD) is a chronic mental illness characterized by changes in mood that alternate between mania and hypomania or between depression and mixed states, often associated with functional impairment. Although effective pharmacological and non-pharmacological treatments are available, several patients with BD remain symptomatic. The advance in the understanding of the neurobiology underlying BD could help in the identification of new therapeutic targets as well as biomarkers for early detection, prognosis, and response to treatment in BD. In this review, we discuss genetic, epigenetic, molecular, physiological and neuroimaging findings associated with the neurobiology of BD. Despite the advances in the pathophysiological knowledge of BD, the diagnosis and management of the disease are still essentially clinical. Given the complexity of the brain and the close relationship between environmental exposure and brain function, initiatives that incorporate genetic, epigenetic, molecular, physiological, clinical, environmental data, and brain imaging are necessary to produce information that can be translated into prevention and better outcomes for patients with BD.


Assuntos
Transtorno Bipolar , Afeto , Transtorno Bipolar/diagnóstico por imagem , Transtorno Bipolar/genética , Encéfalo/diagnóstico por imagem , Humanos , Neurobiologia , Neuroimagem
15.
Curr Psychiatry Rep ; 22(5): 24, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32318888

RESUMO

PURPOSE OF REVIEW: We review the ways in which stem cells are used in psychiatric disease research, including the related advances in gene editing and directed cell differentiation. RECENT FINDINGS: The recent development of induced pluripotent stem cell (iPSC) technologies has created new possibilities for the study of psychiatric disease. iPSCs can be derived from patients or controls and differentiated to an array of neuronal and non-neuronal cell types. Their genomes can be edited as desired, and they can be assessed for a variety of phenotypes. This makes them especially interesting for studying genetic variation, which is particularly useful today now that our knowledge on the genetics of psychiatric disease is quickly expanding. The recent advances in cell engineering have led to powerful new methods for studying psychiatric illness including schizophrenia, bipolar disorder, and autism. There is a wide array of possible applications as illustrated by the many examples from the literature, most of which are cited here.


Assuntos
Transtorno Bipolar , Células-Tronco Pluripotentes Induzidas , Esquizofrenia , Transtorno Bipolar/genética , Humanos , Neurônios , Fenótipo
16.
Nat Genet ; 52(4): 437-447, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32231276

RESUMO

Minimal phenotyping refers to the reliance on the use of a small number of self-reported items for disease case identification, increasingly used in genome-wide association studies (GWAS). Here we report differences in genetic architecture between depression defined by minimal phenotyping and strictly defined major depressive disorder (MDD): the former has a lower genotype-derived heritability that cannot be explained by inclusion of milder cases and a higher proportion of the genome contributing to this shared genetic liability with other conditions than for strictly defined MDD. GWAS based on minimal phenotyping definitions preferentially identifies loci that are not specific to MDD, and, although it generates highly predictive polygenic risk scores, the predictive power can be explained entirely by large sample sizes rather than by specificity for MDD. Our results show that reliance on results from minimal phenotyping may bias views of the genetic architecture of MDD and impede the ability to identify pathways specific to MDD.


Assuntos
Transtorno Depressivo Maior/genética , Predisposição Genética para Doença/genética , Adulto , Idoso , Transtorno Bipolar/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Sensibilidade e Especificidade
17.
J Clin Neurosci ; 78: 264-268, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32279906

RESUMO

The aim of this study to investigate the genetic polymorphisms in macrophage inhibitory factor (MIF) and mannose-binding lectin 2 (MBL2) gene in schizophrenia (SCZ) or bipolar disorder (BD) patients with attempted suicide by comparing with a non-attempted SCZ or BD patients and healthy controls. A sample of 108 patients with SCZ, 100 patients with BD and 100 healthy volunteers were included in the study. SCID-I was used to confirm the diagnosis according to DSM-IV-TR criteria. The patients were evaluated by data forms that included sociodemographic, suicidal behavior and symptom severity information. PCR-RFLP was used to determine MIF and MBL2 gene polymorphisms from DNA material. Our results demonstrated that the distributions of MBL2 genotype (AA, AB, BB), combined genotype (AA, AB/BB) and the allele frequencies (A, B) of attempted suicide patients in SCZ were significantly different from the non-attempted SCZ patients. The distributions of the MBL2 genotype of attempted suicide patients in SCZ were significantly different from the control group. The distributions of MIF genotype (GG, GC, CC), combined genotype (GG, GC/CC) and the allele frequencies (G, C) of attempted suicide patients in BD were significantly different from the non-attempted BD patients or control group. In summary MBL2 gene polymorphism may be associated with attempted suicide in SCZ and MIF gene polymorphism might be associated with attempted suicide in BD. However, further studies with other gene variants in different ethnic populations are needed to address the exact role of these polymorphisms in SCZ or BD.


Assuntos
Transtorno Bipolar/genética , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Lectina de Ligação a Manose/genética , Polimorfismo Genético/genética , Esquizofrenia/genética , Tentativa de Suicídio , Adulto , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/diagnóstico , Psicologia do Esquizofrênico , Tentativa de Suicídio/psicologia
18.
Psychiatry Res ; 286: 112865, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32114208

RESUMO

Bipolar disorder (BD) may be associated with accelerated cellular aging. However, previous studies on telomere length (TL), an important biomarker of cellular aging, have yielded mixed results in BD. We aimed to evaluate the hypothesis that BD is associated with telomere shortening and whether this is counteracted by long-term lithium treatment. We also sought to determine whether long-term lithium treatment is associated with increased expression of telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase. We determined TL and TERT expression in 100 BD I patients and 100 healthy controls. We also genotyped three single nucleotide polymorphisms associated with TL. TERT expression was significantly increased in BD I patients currently on lithium treatment. TERT expression was also significantly positively correlated with duration of lithium treatment in patients treated for 24 months or more. However, we did not find any significant effect of lithium treatment on TL. Neither did we find significant differences in TL between BD patients and controls. We suggest that long-term lithium treatment is associated with an increase in the expression of TERT. We hypothesize that an increase in TERT expression may contribute to lithium's mood stabilizing and neuroprotective properties by improving mitochondrial function and decreasing oxidative stress.


Assuntos
Envelhecimento/metabolismo , Antimaníacos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Senescência Celular/genética , Compostos de Lítio/uso terapêutico , Lítio/uso terapêutico , Telomerase/metabolismo , Adulto , Envelhecimento/genética , Transtorno Bipolar/sangue , Senescência Celular/efeitos dos fármacos , Feminino , Humanos , Compostos de Lítio/farmacologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/genética , Reação em Cadeia da Polimerase em Tempo Real , Telomerase/efeitos dos fármacos , Telomerase/genética , Telômero/efeitos dos fármacos , Telômero/genética , Telômero/metabolismo , Homeostase do Telômero/genética , Encurtamento do Telômero/efeitos dos fármacos , Encurtamento do Telômero/genética
19.
Nat Neurosci ; 23(4): 510-519, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32203495

RESUMO

Specific cell populations may have unique contributions to schizophrenia but may be missed in studies of homogenate tissue. Here laser capture microdissection followed by RNA sequencing (LCM-seq) was used to transcriptomically profile the granule cell layer of the dentate gyrus (DG-GCL) in human hippocampus and contrast these data to those obtained from bulk hippocampal homogenate. We identified widespread cell-type-enriched aging and genetic effects in the DG-GCL that were either absent or directionally discordant in bulk hippocampus data. Of the ~9 million expression quantitative trait loci identified in the DG-GCL, 15% were not detected in bulk hippocampus, including 15 schizophrenia risk variants. We created transcriptome-wide association study genetic weights from the DG-GCL, which identified many schizophrenia-associated genetic signals not found in transcriptome-wide association studies from bulk hippocampus, including GRM3 and CACNA1C. These results highlight the improved biological resolution provided by targeted sampling strategies like LCM and complement homogenate and single-nucleus approaches in human brain.


Assuntos
Giro Denteado/metabolismo , Predisposição Genética para Doença , Neurônios/metabolismo , Esquizofrenia/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/metabolismo , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Locos de Características Quantitativas , Esquizofrenia/metabolismo , Transcriptoma , Adulto Jovem
20.
Proc Natl Acad Sci U S A ; 117(8): 4392-4399, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32041882

RESUMO

The pathogenesis of bipolar disorder (BD) has remained enigmatic, largely because genetic animal models based on identified susceptible genes have often failed to show core symptoms of spontaneous mood cycling. However, pedigree and induced pluripotent stem cell (iPSC)-based analyses have implicated that dysfunction in some key signaling cascades might be crucial for the disease pathogenesis in a subpopulation of BD patients. We hypothesized that the behavioral abnormalities of patients and the comorbid metabolic abnormalities might share some identical molecular mechanism. Hence, we investigated the expression of insulin/synapse dually functioning genes in neurons derived from the iPSCs of BD patients and the behavioral phenotype of mice with these genes silenced in the hippocampus. By these means, we identified synaptotagmin-7 (Syt7) as a candidate risk factor for behavioral abnormalities. We then investigated Syt7 knockout (KO) mice and observed nocturnal manic-like and diurnal depressive-like behavioral fluctuations in a majority of these animals, analogous to the mood cycling symptoms of BD. We treated the Syt7 KO mice with clinical BD drugs including olanzapine and lithium, and found that the drug treatments could efficiently regulate the behavioral abnormalities of the Syt7 KO mice. To further verify whether Syt7 deficits existed in BD patients, we investigated the plasma samples of 20 BD patients and found that the Syt7 mRNA level was significantly attenuated in the patient plasma compared to the healthy controls. We therefore concluded that Syt7 is likely a key factor for the bipolar-like behavioral abnormalities.


Assuntos
Transtorno Bipolar/metabolismo , Transtorno Bipolar/psicologia , Sinaptotagminas/metabolismo , Adulto , Animais , Comportamento , Transtorno Bipolar/sangue , Transtorno Bipolar/genética , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Sinaptotagminas/genética , Adulto Jovem
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