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1.
Psychiatr Danub ; 31(3): 347-354, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31596828

RESUMO

BACKGROUND: The role of sirtuins as a pathogenetic element of some mental disorders is becoming increasingly more common. They participate in many cellular processes, such as ageing, transcription, apoptosis, inflammatory processes, post-translational modification of proteins, gene transcription silencing, activation of DNA repair mechanisms, and regulation of many metabolic processes. The aim of this paper is to verify the statistical hypothesis assuming the difference in expression at the level of mRNA in genes for sirtuins 1-7 between patients with recurrent depressive disorders (rDD) and patients from the control group, and the hypothesis assuming the relation between the expression at the level of mRNA for these genes and clinical variables in the course of recurrent depressive disorders. SUBJECTS AND METHODS: A total of 198 individuals took part in the study (rDD gropup, N=99; control group, N=99). RESULTS: SIR-1 and SIR-6 expression at the mRNA level was significantly higher among the people with rDD as compared to the subjects from the control group. A reversed relationship was observed for SIR-2, SIR-3, SIR-4 and SIR-5. Statistically significant correlations were observed only in the case of SIR-1 and the number of depression episodes (negative relationship), as well as SIR-5 and the severity of depression measured by the Hamilton Depression Rating Scale (positive relationship). CONCLUSIONS: Expression at the mRNA level for selected sirtuins is a factor that significantly differentiates people with depressive episodes from healthy ones. SIR-1 and SIR-6 expression at the mRNA level was significantly higher among the people with depression as compared to the subjects from the control group. A reversed relationship (also statistically significant) was observed for SIR-2, SIR-3, SIR-4 and SIR-5.


Assuntos
Transtorno Depressivo Maior/genética , Regulação da Expressão Gênica , Sirtuínas/genética , Doença Crônica , Humanos , RNA Mensageiro/análise , RNA Mensageiro/genética
2.
Medicine (Baltimore) ; 98(28): e16373, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305436

RESUMO

BACKGROUND: Prenatal exposure to depression has been considered as a risk factor for adverse childhood, while it is accompanied by unknown molecular mechanisms. The aim of this study was to identify differentially expressed genes (DEGs) and associated biological processes between cord blood samples from neonates born to mothers who exposed to major depressive disorder (MDD) and healthy mothers. METHODS: The microarray data GSE114852 were downloaded to analyze the mRNA expression profiles of umbilical cord blood with 31 samples exposed to prenatal MDD and 62 samples with healthy mothers. Kyoto Encyclopedia of Genes and Genomes pathway and Gene ontology enrichment analyses were conducted to identify associated biochemical pathways and functional categories of the DEGs. The protein-protein interaction network was constructed and the top 10 hub genes in the network were predicted. RESULTS: The results showed several immunity related processes, such as "phagosome", "Epstein-Barr virus infection", "proteasome", "positive regulation of I-kappaB kinase/NF-kappaB signaling", "interferon-gamma-mediated signaling pathway", and "tumor necrosis factor" presented significant differences between two groups. Most of the hub genes (for example PSMD2, PSMD6, PSMB8, PSMB9) were also associated with immune pathways. CONCLUSION: This bioinformatic analysis demonstrated immune-mediated mechanisms might play a fatal role in abnormalities in fetal gene expression profiles caused by prenatal MDD.


Assuntos
Transtorno Depressivo Maior , Sangue Fetal/metabolismo , Complicações na Gravidez , Biologia Computacional , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/genética , Feminino , Expressão Gênica , Humanos , Gravidez , Complicações na Gravidez/sangue , Complicações na Gravidez/genética , RNA Mensageiro/sangue
3.
BMC Med Genet ; 20(1): 104, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31185929

RESUMO

BACKGROUND: A multidirectional relationship has been demonstrated between myocardial infarction (MI) and depression. However, the causal genetic factors and molecular mechanisms underlying this interaction remain unclear. The main purpose of this study was to identify potential candidate genes for the interaction between the two diseases. METHODS: Using a bioinformatics approach and existing gene expression data in the biomedical discovery support system (BITOLA), we defined the starting concept X as "Myocardial Infarction" and end concept Z as "Major Depressive Disorder" or "Depressive disorder". All intermediate concepts relevant to the "Gene or Gene Product" for MI and depression were searched. Gene expression data and tissue-specific expression of potential candidate genes were evaluated using the Human eFP (electronic Fluorescent Pictograph) Browser, and intermediate concepts were filtered by manual inspection. RESULTS: Our analysis identified 128 genes common to both the "MI" and "depression" text mining concepts. Twenty-three of the 128 genes were selected as intermediates for this study, 9 of which passed the manual filtering step. Among the 9 genes, LCAT, CD4, SERPINA1, IL6, and PPBP failed to pass the follow-up filter in the Human eFP Browser, due to their low levels in the heart tissue. Finally, four genes (GNB3, CNR1, MTHFR, and NCAM1) remained. CONCLUSIONS: GNB3, CNR1, MTHFR, and NCAM1 are putative new candidate genes that may influence the interactions between MI and depression, and may represent potential targets for therapeutic intervention.


Assuntos
Biologia Computacional/métodos , Mineração de Dados/métodos , Transtorno Depressivo Maior/genética , Predisposição Genética para Doença/genética , Infarto do Miocárdio/genética , Perfilação da Expressão Gênica/métodos , Perfilação da Expressão Gênica/estatística & dados numéricos , Humanos , Reprodutibilidade dos Testes
4.
Nat Genet ; 51(5): 793-803, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043756

RESUMO

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.


Assuntos
Transtorno Bipolar/genética , Loci Gênicos , Transtorno Bipolar/classificação , Estudos de Casos e Controles , Transtorno Depressivo Maior/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Transtornos Psicóticos/genética , Esquizofrenia/genética , Biologia de Sistemas
5.
Medicine (Baltimore) ; 98(19): e15456, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31083176

RESUMO

Venlafaxine is one of commonly prescribed antidepressants for major depressive disorder (MDD). Accumulated evidence implicates the involvement of glutamatergic receptors in the pathophysiology of MDD and antidepressant treatment.By using 193 MDD patients who have been taking venlafaxine for 6 weeks, we investigated whether single nucleotide polymorphisms (SNPs) in glutamate ionotropic receptor kainate type subunit 4 (GRIK4), glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) and glutamate metabotropic receptor 7 (GRM7) were associated with treatment response. 14 SNPs were selected randomly depended on association studies. Efficacy of treatment was determined by 17-item of Hamilton Rating Scale. Allele and genotype frequencies were compared between responders and non-responders.After adjusting by the false discovery rate (FDR), rs6589847 and rs56275759 in GRIK4 and rs9870680 in GRM7 showed associating with venlafaxine treatment response at week 6. (FDR: P = .018, P = .042, and P = .040, respectively).Our results indicated that genetic variants in the GRIK4 and GRM7 may associate with the treatment response in MDD patients treated by venlafaxine.


Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Receptores de Ácido Caínico/genética , Receptores de Glutamato Metabotrópico/genética , Cloridrato de Venlafaxina/uso terapêutico , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Masculino , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Receptores de AMPA/genética , Resultado do Tratamento
6.
Int J Mol Sci ; 20(8)2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31018568

RESUMO

Despite numerous studies on major depressive disorder (MDD) susceptibility, the precise underlying molecular mechanism has not been elucidated which restricts the development of etiology-based disease-modifying drug. Major depressive disorder treatment is still symptomatic and is the leading cause of (~30%) failure of the current antidepressant therapy. Here we comprehended the probable genes and pathways commonly associated with antidepressant response and MDD. A systematic review was conducted, and candidate genes/pathways associated with antidepressant response and MDD were identified using an integrative genetics approach. Initially, single nucleotide polymorphisms (SNPs)/genes found to be significantly associated with antidepressant response were systematically reviewed and retrieved from the candidate studies and genome-wide association studies (GWAS). Also, significant variations concerning MDD susceptibility were extracted from GWAS only. We found 245 (Set A) and 800 (Set B) significantly associated genes with antidepressant response and MDD, respectively. Further, gene set enrichment analysis revealed the top five co-occurring molecular pathways (p ≤ 0.05) among the two sets of genes: Cushing syndrome, Axon guidance, cAMP signaling pathway, Insulin secretion, and Glutamatergic synapse, wherein all show a very close relation to synaptic plasticity. Integrative analyses of candidate gene and genome-wide association studies would enable us to investigate the putative targets for the development of disease etiology-based antidepressant that might be more promising than current ones.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Inibidores de Captação de Serotonina/uso terapêutico , Antidepressivos/farmacologia , AMP Cíclico/metabolismo , Transtorno Depressivo Maior/metabolismo , Estudo de Associação Genômica Ampla , Genômica/métodos , Humanos , Inibidores de Captação de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fluxo de Trabalho
7.
Int J Mol Sci ; 20(8)2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31027150

RESUMO

Alpha-synuclein (SNCA) is a small membrane protein that plays an important role in neuro-psychiatric diseases. It is best known for its abnormal subcellular aggregation in Lewy bodies that serves as a hallmark of Parkinson's disease (PD). Due to the high comorbidity of PD with depression, we investigated the role of SNCA in patients suffering from major depressive disorder (MDD). SNCA mRNA expression levels were analyzed in peripheral blood cells of MDD patients and a healthy control group. SNCA mRNA expression was positively correlated with severity of depression as indicated by psychometric assessment. We found a significant increase in SNCA mRNA expression levels in severely depressed patients compared with controls. Thus, SNCA analysis could be a helpful target in the search for biomarkers of MDD.


Assuntos
Transtorno Depressivo Maior/genética , Regulação da Expressão Gênica , alfa-Sinucleína/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , alfa-Sinucleína/metabolismo
8.
PLoS Genet ; 15(4): e1008060, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31022172

RESUMO

The promise of personalized genomic medicine is that knowledge of a person's gene sequences and activity will facilitate more appropriate medical interventions, particularly drug prescriptions, to reduce the burden of disease. Early successes in oncology and pediatrics have affirmed the power of positive diagnosis and are mostly based on detection of one or a few mutations that drive the specific pathology. However, genetically more complex diseases require the development of polygenic risk scores (PRSs) that have variable accuracy. The rarity of events often means that they have necessarily low precision: many called positives are actually not at risk, and only a fraction of cases are prevented by targeted therapy. In some situations, negative prediction may better define the population at low risk. Here, I review five conditions across a broad spectrum of chronic disease (opioid pain medication, hypertension, type 2 diabetes, major depression, and osteoporotic bone fracture), considering in each case how genetic prediction might be used to target drug prescription. This leads to a call for more research designed to evaluate genetic likelihood of response to therapy and a call for evaluation of PRS, not just in terms of sensitivity and specificity but also with respect to potential clinical efficacy.


Assuntos
Herança Multifatorial , Medicina de Precisão/métodos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/genética , Masculino , Mutação , Transtornos Relacionados ao Uso de Opioides/genética , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Osteoporose/genética , Osteoporose/prevenção & controle , Testes Farmacogenômicos/métodos , Medicina Preventiva/métodos , Fatores de Risco
9.
PLoS Genet ; 15(4): e1008009, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30951530

RESUMO

Recent and classical work has revealed biologically and medically significant subtypes in complex diseases and traits. However, relevant subtypes are often unknown, unmeasured, or actively debated, making automated statistical approaches to subtype definition valuable. We propose reverse GWAS (RGWAS) to identify and validate subtypes using genetics and multiple traits: while GWAS seeks the genetic basis of a given trait, RGWAS seeks to define trait subtypes with distinct genetic bases. Unlike existing approaches relying on off-the-shelf clustering methods, RGWAS uses a novel decomposition, MFMR, to model covariates, binary traits, and population structure. We use extensive simulations to show that modelling these features can be crucial for power and calibration. We validate RGWAS in practice by recovering a recently discovered stress subtype in major depression. We then show the utility of RGWAS by identifying three novel subtypes of metabolic traits. We biologically validate these metabolic subtypes with SNP-level tests and a novel polygenic test: the former recover known metabolic GxE SNPs; the latter suggests subtypes may explain substantial missing heritability. Crucially, statins, which are widely prescribed and theorized to increase diabetes risk, have opposing effects on blood glucose across metabolic subtypes, suggesting the subtypes have potential translational value.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Modelos Genéticos , Herança Multifatorial , Fenótipo , Algoritmos , Glicemia/efeitos dos fármacos , Glicemia/genética , Análise por Conglomerados , Simulação por Computador , Doença das Coronárias/sangue , Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/genética , Transtorno Depressivo Maior/classificação , Transtorno Depressivo Maior/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lipídeos/sangue , Polimorfismo de Nucleotídeo Único , Estado Pré-Diabético/genética , Locos de Características Quantitativas
10.
Nat Commun ; 10(1): 1941, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31028273

RESUMO

Mendelian randomization (MR) has emerged as a major tool for the investigation of causal relationship among traits, utilizing results from large-scale genome-wide association studies. Bias due to horizontal pleiotropy, however, remains a major concern. We propose a novel approach for robust and efficient MR analysis using large number of genetic instruments, based on a novel spike-detection algorithm under a normal-mixture model for underlying effect-size distributions. Simulations show that the new method, MRMix, provides nearly unbiased or/and less biased estimates of causal effects compared to alternative methods and can achieve higher efficiency than comparably robust estimators. Application of MRMix to publicly available datasets leads to notable observations, including identification of causal effects of BMI and age-at-menarche on the risk of breast cancer; no causal effect of HDL and triglycerides on the risk of coronary artery disease; a strong detrimental effect of BMI on the risk of major depressive disorder.


Assuntos
Algoritmos , Neoplasias da Mama/genética , Doença da Artéria Coronariana/genética , Transtorno Depressivo Maior/genética , Genoma Humano , Análise da Randomização Mendeliana/estatística & dados numéricos , Fatores Etários , Índice de Massa Corporal , Neoplasias da Mama/sangue , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/etiologia , HDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/etiologia , Conjuntos de Dados como Assunto , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/etiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Menarca/sangue , Menarca/genética , Característica Quantitativa Herdável , Fatores de Risco , Triglicerídeos/sangue
11.
Int J Mol Sci ; 20(4)2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30813226

RESUMO

Gender differences play a pivotal role in the pathophysiology and treatment of major depressive disorder. This is strongly supported by a mean 2:1 female-male ratio of depression consistently observed throughout studies in developed nations. Considering the urgent need to tailor individualized treatment strategies to fight depression more efficiently, a more precise understanding of gender-specific aspects in the pathophysiology and treatment of depressive disorders is fundamental. However, current treatment guidelines almost entirely neglect gender as a potentially relevant factor. Similarly, the vast majority of animal experiments analysing antidepressant treatment in rodent models exclusively uses male animals and does not consider gender-specific effects. Based on the growing interest in innovative and rapid-acting treatment approaches in depression, such as the administration of ketamine, its metabolites or electroconvulsive therapy, this review article summarizes the evidence supporting the importance of gender in modulating response to rapid acting antidepressant treatment. We provide an overview on the current state of knowledge and propose a framework for rodent experiments to ultimately decode gender-dependent differences in molecular and behavioural mechanisms involved in shaping treatment response.


Assuntos
Antidepressivos/farmacologia , Animais , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Eletroconvulsoterapia , Feminino , Humanos , Ketamina/metabolismo , Masculino , Resultado do Tratamento
12.
Clin Neuropharmacol ; 42(2): 32-36, 2019 Mar/Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30875344

RESUMO

Major depressive disorder (MDD) is a common mental disorder. Venlafaxine (VEN) is used to treat patients with MDD as an antidepressant of serotonin-norepinephrine reuptake inhibitor. In addition, current reports reveal that CYP enzymes mediate its metabolism, thereby affecting the treatment efficacy. The aim of this study was to test whether the genetic polymorphisms of CYP1A2 are associated with remission after VEN treatment for MDD. A total of 175 Han Chinese depressed patients have been recruited to accept a 6-week treatment with VEN. Three single-nucleotide polymorphisms of CYP1A2 were selected from dbSNP and previous literature to compare the allele and genotype frequencies between remitters and nonremitters. The A 17-item Hamilton Depression Scale was used to access the improvement of patients' depressive symptoms from the baseline to endpoint. A logistic regression analysis for remission was conducted. Between remitters and nonremitters, the allele and genotype frequencies of single-nucleotide polymorphism rs2470890 demonstrated significant differences. They still had significant differences between remitters and nonremitters after controlling baseline Hamilton Depression Scale scores, sex, and age in logistic regression. Our results suggest that the single-nucleotide polymorphism rs2470890 of CYP1A2 gene might be associated with treatment remission after VEN treatment in patients with MDD.


Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , Citocromo P-450 CYP1A2/genética , Transtorno Depressivo Maior/genética , Polimorfismo de Nucleotídeo Único/genética , Cloridrato de Venlafaxina/uso terapêutico , Adulto , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão/métodos , Resultado do Tratamento , Adulto Jovem
13.
Actas esp. psiquiatr ; 47(1): 1-6, ene.-feb. 2019. graf, tab
Artigo em Espanhol | IBECS | ID: ibc-182172

RESUMO

Introducción. De acuerdo a la Organización Mundial de la Salud el suicidio se encuentra en las principales causas de muerte en niños y adolescentes. La depresión es el trastorno más asociado a la conducta suicida. Existe cada vez mayor evidencia respecto a que la conducta suicida tiene una fuerte contribución genética. Varios estudios reportan una asociación entre el genotipo "SS" y el alelo "S" del polimorfismo 5-HTTLPR del gen del transportador de serotonina y la conducta suicida. El objetivo del estudio fue establecer la asociación de las variantes del gen del transportador de serotonina con el intento suicida y la comorbilidad en pacientes adolescentes deprimidos. Metodología. Se compararon las frecuencias de genotipo "SS" y del alelo "S" entre una muestra de 200 adolescentes evaluados con la entrevista semi-estructurada K-SADSPL y una muestra de 235 controles sanos. La genotipificacion del polimorfismo 5-HTTLPR se realizó mediante PCR. Resultados. El análisis de las frecuencias de genotipos y alelos mostro diferencia estadísticamente significativas entre los grupos (Genotipos: x2=11,1, gl=2, p=0,004; Alelos: x2=11,9, gl=1, p=0,0009). No existió asociación con los trastornos comorbidos. Conclusiones. Los resultados apoyan la hipótesis de que el gen del transportador de serotonina, específicamente el alelo s y el genotipo ss del polimorfismo 5-HTTLPR, se encuentran relacionados con la historia de depresión e intento suicida en adolescentes


Introduction. The World Health Organization reports that suicide is among the leading causes of death for young people. Depression is the most frequently related disorder with suicidal behaviors. There is increasing evidence that suicidal behavior has a strong genetic contribution. Several studies report an association between the genotype "SS" and the "S" allele of the 5-HTTLPR polymorphism of the serotonin transporter gene and suicidal behavior. The aim of the study was to determine the association of variants of the serotonin transporter gene with suicidal attempt and comorbidity in depressed adolescents. Methods. The frequencies of ss genotypes and s allele were compared between a sample of 200 adolescents with a diagnosis of depression and the antecedent of a suicide attempt who were evaluated with K-SADS-PL and a group of 235 healthy controls. Genotyping of the 5-HTTLPR polymorphism was performed by PCR. Results. Analysis of the frequencies of genotypes and alleles showed a statistically significant difference between the groups (Genotypes: x2=11.1, df=2, p=0.004, Alleles: x2=11.9, df=1, p=0.0009). There were no associations with comorbid disorders. Conclusions. The results support the hypothesis that the serotonin transporter gene, specifically the s allele and the ss genotype of the 5-HTTLPR polymorphism, are related to the history of depression and suicide attempt in adolescents


Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Transtorno Depressivo Maior/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Tentativa de Suicídio , Alelos , Estudos de Casos e Controles , Comorbidade , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/psicologia , Estudos de Associação Genética , México/epidemiologia , Polimorfismo Genético/genética , Tentativa de Suicídio/psicologia , Tentativa de Suicídio/estatística & dados numéricos
14.
Cell Tissue Res ; 377(1): 21-43, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30778732

RESUMO

The increasing number of individuals with comorbidities poses an urgent need to improve the management of patients with multiple co-existing diseases. Among these comorbidities, chronic pain and mood disorders, two long-lasting disabling conditions that significantly reduce the quality of life, could be cited first. The recent development of animal models accelerated the studies focusing on the underlying mechanisms of the chronic pain and depression/anxiety comorbidity. This review provides an overview of clinical and pre-clinical studies performed over the past two decades addressing the molecular aspects of the comorbid relationship of chronic pain and depression. We thus focused on the studies that investigated the molecular characteristics of the comorbid relationship between chronic pain and mood disorders, especially major depressive disorders, from the genetic and epigenetic point of view to key neuromodulators which have been shown to play an important role in this comorbidity.


Assuntos
Dor Crônica/epidemiologia , Dor Crônica/genética , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Animais , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/genética , Monoaminas Biogênicas/farmacologia , Monoaminas Biogênicas/uso terapêutico , Dor Crônica/tratamento farmacológico , Comorbidade , Transtorno Depressivo Maior/tratamento farmacológico , Modelos Animais de Doenças , Epigênese Genética , Humanos , Camundongos , Qualidade de Vida , Ratos , Fatores de Transcrição/metabolismo
15.
J Affect Disord ; 249: 336-346, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30802699

RESUMO

BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability worldwide, and over half of patients do not achieve symptom remission following an initial antidepressant course. Despite evidence implicating a strong genetic basis for the pathophysiology of MDD, there are no adequately validated biomarkers of treatment response routinely used in clinical practice. Pharmacoepigenetics is an emerging field that has the potential to combine both genetic and environmental information into treatment selection and further the goal of precision psychiatry. However, this field is in its infancy compared to the more established pharmacogenetics approaches. METHODS: We prepared a narrative review using literature searches of studies in English pertaining to pharmacoepigenetics and treatment of depressive disorders conducted in PubMed, Google Scholar, PsychINFO, and Ovid Medicine from inception through January 2019. We reviewed studies of DNA methylation and histone modifications in both humans and animal models of depression. RESULTS: Emerging evidence from human and animal work suggests a key role for epigenetic marks, including DNA methylation and histone modifications, in the prediction of antidepressant response. The challenges of heterogeneity of patient characteristics and loci studied as well as lack of replication that have impacted the field of pharmacogenetics also pose challenges to the development of pharmacoepigenetic tools. Additionally, given the tissue specific nature of epigenetic marks as well as their susceptibility to change in response to environmental factors and aging, pharmacoepigenetic tools face additional challenges to their development. LIMITATIONS: This is a narrative and not systematic review of the literature on the pharmacoepigenetics of antidepressant response. We highlight key studies pertaining to pharmacoepigenetics and treatment of depressive disorders in humans and depressive-like behaviors in animal models, regardless of sample size or methodology. While we discuss DNA methylation and histone modifications, we do not cover microRNAs, which have been reviewed elsewhere recently. CONCLUSIONS: Utilization of genome-wide approaches and reproducible epigenetic assays, careful selection of the tissue assessed, and integration of genetic and clinical information into pharmacoepigenetic tools will improve the likelihood of developing clinically useful tests.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Farmacogenética/métodos , Medicina de Precisão/métodos , Animais , Antidepressivos/uso terapêutico , Metilação de DNA , Depressão , Epigenômica/métodos , Feminino , Humanos , MicroRNAs
16.
Actas Esp Psiquiatr ; 47(1): 1-6, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30724325

RESUMO

INTRODUCTION: The World Health Organization reports that suicide is among the leading causes of death for young people. Depression is the most frequently related disorder with suicidal behaviors. There is increasing evidence that suicidal behavior has a strong genetic contribution. Several studies report an association between the genotype "SS" and the "S" allele of the 5-HTTLPR polymorphism of the serotonin transporter gene and suicidal behavior. The aim of the study was to determine the association of variants of the serotonin transporter gene with suicidal attempt and comorbidity in depressed adolescents. METHODS: The frequencies of ss genotypes and s allele were compared between a sample of 200 adolescents with a diagnosis of depression and the antecedent of a suicide attempt who were evaluated with K-SADS-PL and a group of 235 healthy controls. Genotyping of the 5-HTTLPR polymorphism was performed by PCR. RESULTS: Analysis of the frequencies of genotypes and alleles showed a statistically significant difference between the groups (Genotypes: x2=11.1, df=2, p=0.004, Alleles: x2=11.9, df=1, p=0.0009). There were no associations with comorbid disorders. CONCLUSIONS: The results support the hypothesis that the serotonin transporter gene, specifically the s allele and the ss genotype of the 5-HTTLPR polymorphism, are related to the history of depression and suicide attempt in adolescents.


Assuntos
Transtorno Depressivo Maior/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Tentativa de Suicídio , Adolescente , Alelos , Estudos de Casos e Controles , Criança , Comorbidade , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/psicologia , Feminino , Estudos de Associação Genética , Humanos , Masculino , México/epidemiologia , Polimorfismo Genético/genética , Tentativa de Suicídio/psicologia , Tentativa de Suicídio/estatística & dados numéricos
17.
Nat Neurosci ; 22(3): 343-352, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30718901

RESUMO

Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximize sample size, we meta-analyzed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 genesets associated with depression, including both genes and gene pathways associated with synaptic structure and neurotransmission. An enrichment analysis provided further evidence of the importance of prefrontal brain regions. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant after multiple testing correction. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding etiology and developing new treatment approaches.


Assuntos
Depressão/genética , Transtorno Depressivo Maior/genética , Córtex Pré-Frontal/metabolismo , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Herança Multifatorial , Polimorfismo de Nucleotídeo Único
18.
Transl Psychiatry ; 9(1): 52, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30705256

RESUMO

Major depressive disorder (MDD) is a common and disabling psychiatric disorder. A recent mega analysis of genome-wide association studies (GWASs) identified 44 loci associated with MDD, though most of the genetic etiologies of the MDD/psychological distress remain unclear. To further understand the genetic basis of MDD/psychological distress, we conducted a GWAS in East Asia with more than 10,000 participants of Japanese ancestry who had enrolled in a direct-to-consumer genetic test. After quality control on the genotype data, 10,330 subjects with a total of 8,567,708 imputed SNPs were eligible for the analysis. The participants completed a self-administered questionnaire on their past medical history and health conditions that included the 6-item Kessler screening scale (K6 scale) for psychological distress (cut-off point of 5) and past medical history of MDD, resulting in 3981 subjects assigned to "psychologically distressed group" [cases], and the remaining 6349 subjects were assigned to the "non-psychologically distressed group" [controls]. In this GWAS, we found an association with genome-wide significance at rs6073833 (P = 7.60 × 10-9) in 20q13.12. This is, to the best of our knowledge, the first large-scale GWAS for psychological distress using data from direct-to-consumer (DTC) genetic tests in a population of non-European-ancestry, and the present study thus detected a novel locus significantly associated with psychological distress in the Japanese population.


Assuntos
Transtorno Depressivo Maior/genética , Estresse Psicológico/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
19.
Transl Psychiatry ; 9(1): 14, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718454

RESUMO

Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population-based cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77 × 10-6). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53-kb downstream PIWIL4; p = 4.95 × 10-9; total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46 × 10-8; dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00 × 10-8; dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77 × 10-6). Polygenic risk scores (PRSs) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91 × 10-3). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions.


Assuntos
Depressão/genética , Transtorno Depressivo Maior/genética , Acontecimentos que Mudam a Vida , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Bancos de Espécimes Biológicos , Estudos de Coortes , Depressão/etiologia , Transtorno Depressivo Maior/etiologia , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise de Regressão , Escócia , Reino Unido
20.
Sci Data ; 6: 190010, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30720799

RESUMO

Suicide is one of the leading causes of mortality worldwide; it causes the death of more than one million patients each year. Suicide is a complex, multifactorial phenotype with environmental and genetic factors contributing to the risk of the forthcoming suicide. These factors first generally lead to mental disorders, such as depression, schizophrenia and bipolar disorder, which then become the direct cause of suicide. Here we present a high quality dataset (including processed BAM and VCF files) gained from the high-throughput whole-exome Illumina sequencing of 23 suicide victims - all of whom had suffered from major depressive disorder - and 21 control patients to a depth of at least 40-fold coverage in both cohorts. We identified ~130,000 variants per sample and altogether 442,270 unique variants in the cohort of 44 samples. To our best knowledge, this is the first whole-exome sequencing dataset from suicide victims. We expect that this dataset provides useful information for genomic studies of suicide and depression, and also for the analysis of the Hungarian population.


Assuntos
Transtorno Depressivo Maior/genética , Suicídio , Sequenciamento Completo do Exoma , Estudos de Coortes , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hungria/epidemiologia
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