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1.
Psychol Med ; : 1-12, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31589133

RESUMO

BACKGROUND: Bipolar disorder (BD) is a highly heritable mood disorder with complex genetic architecture and poorly understood etiology. Previous transcriptomic BD studies have had inconsistent findings due to issues such as small sample sizes and difficulty in adequately accounting for confounders like medication use. METHODS: We performed a differential expression analysis in a well-characterized BD case-control sample (Nsubjects = 480) by RNA sequencing of whole blood. We further performed co-expression network analysis, functional enrichment, and cell type decomposition, and integrated differentially expressed genes with genetic risk. RESULTS: While we observed widespread differential gene expression patterns between affected and unaffected individuals, these effects were largely linked to lithium treatment at the time of blood draw (FDR < 0.05, Ngenes = 976) rather than BD diagnosis itself (FDR < 0.05, Ngenes = 6). These lithium-associated genes were enriched for cell signaling and immune response functional annotations, among others, and were associated with neutrophil cell-type proportions, which were elevated in lithium users. Neither genes with altered expression in cases nor in lithium users were enriched for BD, schizophrenia, and depression genetic risk based on information from genome-wide association studies, nor was gene expression associated with polygenic risk scores for BD. CONCLUSIONS: These findings suggest that BD is associated with minimal changes in whole blood gene expression independent of medication use but emphasize the importance of accounting for medication use and cell type heterogeneity in psychiatric transcriptomic studies. The results of this study add to mounting evidence of lithium's cell signaling and immune-related mechanisms.

2.
Nat Neurosci ; 22(7): 1196, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31168101

RESUMO

Several occurrences of the word 'schizophrenia' have been re-worded as 'liability to schizophrenia' or 'schizophrenia risk', including in the title, which should have been "GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability," as well as in Supplementary Figures 1-10 and Supplementary Tables 7-10, to more accurately reflect the findings of the work.

4.
Schizophr Res ; 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31130400

RESUMO

A role for immune processes in the pathogenesis of schizophrenia has been suggested by genetic and epidemiological studies, as well as cross-sectional studies on blood and brain samples. However, results are heterogeneous, which is likely caused by low samples sizes, insufficient control of confounders that influence immune processes, and potentially publication bias. Large hypothesis-free 'omic' studies partially circumvent these problems and could provide further evidence for a role of immune pathways in schizophrenia. In this review we assessed whether the largest genome, transcriptome and methylome studies in schizophrenia to date support a link with the immune system. We constructed an overview of the schizophrenia-associated genes and transcripts that were identified in these large 'omic' studies. We then performed a hypothesis-driven analysis to examine the association and enrichment of immune system-related genes and transcripts in these datasets. Additionally, we reviewed secondary analyses that were previously performed on these 'omic' studies. Except for the link between complement factor 4 (C4), we found limited evidence for a role of microglia and immune processes among genetic risk variants. Transcriptome and methylome studies point towards alterations in immune system related genes, pathways and cells. This includes changes in microglia, as well as complement, nuclear factor-κB, toll-like receptor and interferon signaling pathways. Many of these associated immune-related genes and pathways have been shown to be involved in neurodevelopment and neuronal functioning. Additional replication of these findings is needed, but once further conformation is provided, these findings could be a potentially interesting target for future therapies.

5.
Mol Psychiatry ; 2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31142820

RESUMO

Disruption of persistent, stress-associated memories is relevant for treating posttraumatic stress disorder (PTSD) and related syndromes, which develop in a subset of individuals following a traumatic event. We previously developed a stress-enhanced fear learning (SEFL) paradigm in inbred mice that produces PTSD-like characteristics in a subset of mice, including persistently enhanced memory and heightened cFos in the basolateral amygdala complex (BLC) with retrieval of the remote (30-day-old) stress memory. Here, the contribution of BLC microRNAs (miRNAs) to stress-enhanced memory was investigated because of the molecular complexity they achieve through their ability to regulate multiple targets simultaneously. We performed small-RNA sequencing (smRNA-Seq) and quantitative proteomics on BLC tissue collected from mice 1 month after SEFL and identified persistently changed microRNAs, including mir-135b-5p, and proteins associated with PTSD-like heightened fear expression. Viral-mediated overexpression of mir-135b-5p in the BLC of stress-resilient animals enhanced remote fear memory expression and promoted spontaneous renewal 14 days after extinction. Conversely, inhibition of BLC mir-135b-5p in stress-susceptible animals had the opposite effect, promoting a resilient-like phenotype. mir-135b-5p is highly conserved across mammals and was detected in post mortem human amygdala, as well as human serum samples. The mir-135b passenger strand, mir-135b-3p, was significantly elevated in serum from PTSD military veterans, relative to combat-exposed control subjects. Thus, miR-135b-5p may be an important therapeutic target for dampening persistent, stress-enhanced memory and its passenger strand a potential biomarker for responsivity to a mir-135-based therapeutic.

6.
Neurosci Biobehav Rev ; 96: 127-142, 2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30496762

RESUMO

The human oxytocin (OXT) system is implicated in the regulation of complex social behaviors, as well as in psychopathologies characterized by social deficits. Emerging evidence suggests that variation in epigenetic regulation of the oxytocin receptor gene (OXTR) provides the oxytocin system with flexibility in response to environmental events, especially those occurring during early childhood. Changes in DNA methylation patterns of OXTR associated with these events may reflect biological alterations of social sensitivity. This is often related to an increased risk of developing mental disorders later in life. Here, we systematically reviewed all human studies (n = 30) discussing OXTR methylation in relation to socio-behavioral phenotypes. As such, we provide a complete and up-to-date overview of the literature that will aid future research in the interdisciplinary field of epigenetics and socio-behavioral sciences.

7.
Psychol Med ; : 1-13, 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30303059

RESUMO

BACKGROUND: In a large and comprehensively assessed sample of patients with bipolar disorder type I (BDI), we investigated the prevalence of psychotic features and their relationship with life course, demographic, clinical, and cognitive characteristics. We hypothesized that groups of psychotic symptoms (Schneiderian, mood incongruent, thought disorder, delusions, and hallucinations) have distinct relations to risk factors. METHODS: In a cross-sectional study of 1342 BDI patients, comprehensive demographical and clinical characteristics were assessed using the Structured Clinical Interview for DSM-IV (SCID-I) interview. In addition, levels of childhood maltreatment and intelligence quotient (IQ) were assessed. The relationships between these characteristics and psychotic symptoms were analyzed using multiple general linear models. RESULTS: A lifetime history of psychotic symptoms was present in 73.8% of BDI patients and included delusions in 68.9% of patients and hallucinations in 42.6%. Patients with psychotic symptoms showed a significant younger age of disease onset (ß = -0.09, t = -3.38, p = 0.001) and a higher number of hospitalizations for manic episodes (F11 338 = 56.53, p < 0.001). Total IQ was comparable between groups. Patients with hallucinations had significant higher levels of childhood maltreatment (ß = 0.09, t = 3.04, p = 0.002). CONCLUSIONS: In this large cohort of BDI patients, the vast majority of patients had experienced psychotic symptoms. Psychotic symptoms in BDI were associated with an earlier disease onset and more frequent hospitalizations particularly for manic episodes. The study emphasizes the strength of the relation between childhood maltreatment and hallucinations but did not identify distinct subgroups based on psychotic features and instead reported of a large heterogeneity of psychotic symptoms in BD.

8.
Nat Neurosci ; 21(9): 1161-1170, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30150663

RESUMO

Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.

9.
Eur Neuropsychopharmacol ; 28(6): 743-751, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29779901

RESUMO

Bipolar disorder (BD) patients show aberrant white matter microstructure compared to healthy controls but little is known about the relation with clinical characteristics. We therefore investigated the relation of white matter microstructure with the main pharmacological treatments as well its relation with IQ. Patients with BD (N = 257) and controls (N = 167) underwent diffusion tensor imaging (DTI) and comprehensive clinically assessments including IQ estimates. DTI images were analyzed using tract-based spatial statistics. Fractional anisotropy (FA) and Mean Diffusivity (MD) were determined. Patients had significantly lower FA and higher MD values throughout the white matter skeleton compared to controls. Within the BD patients, lithium use was associated with higher FA and lower MD. Antipsychotic medication use in the BD patients was not associated with FA but, in contrast to lithium, was associated with higher MD. IQ was significantly positively correlated with FA and negatively with MD in patients as well as in controls. In this large DTI study we found evidence for marked differences in FA and MD particularly in (but not restricted to) corpus callosum, between BD patients and controls. This effect was most pronounced in lithium-free patients, implicating that lithium affects white matter microstructure and attenuates differences associated with bipolar disorder. Effects of antipsychotic medication intake were absent in FA and only subtle in MD relative to those of lithium. The abnormal white matter microstructure was associated with IQ but not specifically for either group.

10.
Acad Pediatr ; 18(6): 655-661, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29530583

RESUMO

OBJECTIVE: To investigate the prevalence of adolescent sleep disturbances and their relation to psychosocial difficulties and health risk behaviors with the use of data from a province-wide health survey (n = 16,781). METHODS: Psychosocial difficulties were measured with the Strength and Difficulties Questionnaire. Additional assessments included self-reported sleep disturbances, suicidality, and health risk behaviors including current use of tobacco, alcohol, and drugs, physical inactivity, and compulsive use of multimedia. We used multilevel analyses to investigate the relationhips, including differences, between boys and girls, as well as the mediating role of emotional problems. RESULTS: Just under 20% of adolescents reported sleep disturbances in the previous month. These sleep disturbances were associated with psychosocial problems (odds ratio [OR], 6.42; P < .001), suicidality (OR, 3.90-4.14; P < .001), and all health risk behaviors (OR, 1.62-2.66; P < .001), but not with physical inactivity. We found moderation by gender for the relations between sleep and suicide attempts (OR, 0.38; P < .002) and between sleep and cannabis use (OR, 0.52; P = .002), indicating attenuated relationships in girls compared with boys. Emotional problems partially mediated the relationships between sleep disturbances and multimedia use. CONCLUSIONS: This study reiterates the high prevalence of sleep disturbances during adolescence. These sleep disturbances were strongly related to psychosocial problems and a wide range of health risk behaviors. Although the direction of causality cannot be inferred, this study emphasizes the need for awareness of impaired sleep in adolescents. Moreover, the gender differences in associated suicide attempts and cannabis use call for further research into tailored intervention strategies.

11.
J Affect Disord ; 223: 59-64, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28728036

RESUMO

OBJECTIVES: Bipolar disorder type-I (BD-I) patients show a lower Intelligence Quotient (IQ) and smaller brain volumes as compared with healthy controls. Considering that in healthy individuals lower IQ is related to smaller total brain volume, it is of interest to investigate whether IQ deficits in BD-I patients are related to smaller brain volumes and to what extent smaller brain volumes can explain differences between premorbid IQ estimates and IQ after a diagnosis of BD-I. METHODS: Magnetic resonance imaging brain scans, IQ and premorbid IQ scores were obtained from 195 BDI patients and 160 controls. We studied the relationship of (global, cortical and subcortical) brain volumes with IQ and IQ change. Additionally, we investigated the relationship between childhood trauma, lithium- and antipsychotic use and IQ. RESULTS: Total brain volume and IQ were positively correlated in the entire sample. This correlation did not differ between patients and controls. Although brain volumes mediated the relationship between BD-I and IQ in part, the direct relationship between the diagnosis and IQ remained significant. Childhood trauma and use of lithium and antipsychotic medication did not affect the relationship between brain volumes and IQ. However, current lithium use was related to lower IQ in patients. CONCLUSIONS: Our data suggest a similar relationship between brain volume and IQ in BD-I patients and controls. Smaller brain volumes only partially explain IQ deficits in patients. Therefore, our findings indicate that in addition to brain volumes and lithium use other disease factors play a role in IQ deficits in BD-I patients.


Assuntos
Transtorno Bipolar/fisiopatologia , Encéfalo/patologia , Inteligência/fisiologia , Adulto , Idoso , Transtorno Bipolar/diagnóstico , Encéfalo/diagnóstico por imagem , Estudos Transversais , Feminino , Humanos , Testes de Inteligência , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Adulto Jovem
12.
Acad Pediatr ; 17(6): 642-648, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28456580

RESUMO

OBJECTIVE: Previous research suggests that cognitive functioning is associated with the risk of several adult psychiatric disorders. In this study we investigated whether adolescents who perform worse than expected at secondary school are at a higher risk for general mental health problems. METHODS: In a cross-sectional survey comprising 10,866 Dutch adolescents aged 13 to 16 years, underachievement at secondary school was defined as the discrepancy between predicted school grade and actual grade 1 or 3 years later. Mental health problems were assessed using the Strengths and Difficulties Questionnaire. We investigated the association of underachievement with mental health problems using logistic regression, adjusting for potential confounders. RESULTS: Underachievement was associated with general psychopathology in pupils aged 13 to 14 years (odds ratio [OR], 1.86; 95% confidence interval [CI], 1.47-2.37) and in pupils aged 15 to 16 years (OR, 2.05; 95% CI, 1.67-2.52) in a multivariate analysis including sociodemographic factors. The association between underachievement and mental health problems was attenuated when school factors such as teacher advice and interaction between underachievement and teacher advice were added, but underachievement remained significantly associated with mental health problems in adolescents in the higher educational tracks (pupils aged 13-14 years: OR, 2.22; 95% CI, 1.07-4.60 and OR, 2.41; 95% CI, 1.10-5.30, age 15-16 years: OR, 2.63; 95% CI, 1.38-5.03). In the multivariate analysis including the interaction between underachievement and teacher advice, a significant interaction effect occurs between underachievement and teacher advice in the higher tracks. Values of OR and CI are given for each significant interaction term. In the younger age group (pupils aged 13-14 years) this results in 2 sets of OR and CI. This association was most pronounced for the hyperactivity subscale of the Strengths and Difficulties Questionnaire. CONCLUSIONS: Underachievement at secondary school is associated with general mental health problems, especially with hyperactivity symptoms, in pupils who started at high educational tracks.


Assuntos
Comportamento do Adolescente/psicologia , Transtornos Mentais/psicologia , Baixo Rendimento Escolar , Sucesso Acadêmico , Adolescente , Estudos Transversais , Docentes , Feminino , Humanos , Relações Interpessoais , Modelos Logísticos , Masculino , Saúde Mental , Países Baixos , Estudantes , Inquéritos e Questionários
13.
Psychiatry Res Neuroimaging ; 262: 71-80, 2017 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-28236715

RESUMO

We investigate how the sleep disruptions and irregular physical activity levels that are prominent features of bipolar disorder (BD) relate to white matter microstructure in patients and controls. Diffusion tension imaging (DTI) and 14-day actigraphy recordings were obtained in 51 BD I patients and 55 age-and-gender-matched healthy controls. Tract-based spatial statistics (TBSS) was used for voxelwise analysis of the association between fractional anisotropy (FA) and sleep and activity characteristics in the overall sample. Next, we investigated whether the relation between sleep and activity and DTI measures differed for patients and controls. Physical activity was related to increased integrity of white matter microstructure regardless of bipolar diagnosis. The relationship between sleep and white matter microstructure was more equivocal; we found an expected association between higher FA and effective sleep in controls but opposite patterns in bipolar patients. Confounding factors such as antipsychotic medication use are a likely explanation for these contrasting findings and highlight the need for further study of medication-related effects on white matter integrity.


Assuntos
Transtorno Bipolar/diagnóstico por imagem , Exercício/fisiologia , Sono/fisiologia , Substância Branca/diagnóstico por imagem , Adulto , Anisotropia , Transtorno Bipolar/fisiopatologia , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Substância Branca/fisiopatologia
14.
J Affect Disord ; 208: 248-254, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-27792970

RESUMO

OBJECTIVES: Disturbances in sleep and waking patterns are highly prevalent during mood episodes in bipolar disorder. The question remains whether these disturbances persist during phases of euthymia and whether they are heritable traits of bipolar disorder. The current study investigates objective sleep measures in a large sample of bipolar I patients, non-affected siblings and controls. METHODS: A total of 107 bipolar disorder I patients, 74 non-affected siblings, and 80 controls were included. Sleep was measured with actigraphy over the course of 14 days. Seven sleep parameters were analyzed for group differences and their relationship with age at onset, number of episodes and psychotic symptoms using linear mixed model analysis to account for family dependencies. RESULTS: Patients had a longer sleep duration and later time of sleep offset compared to the non-affected siblings but these differences were entirely attributable to differences in mood symptoms. We found no difference between patients and controls or siblings and controls when the analyses were restricted to euthymic patients. None of the bipolar illness characteristics were associated with sleep. LIMITATIONS: Medication use was not taken into account which may have influenced our findings and controls were younger compared to non-affected siblings. CONCLUSIONS: In the largest study to date, our findings suggest that recovered bipolar I patients and their siblings do not experience clinically significant sleep disturbances. Sleep disturbances are primarily a reflection of current mood state, but are unrelated to the course of the disorder.


Assuntos
Transtorno Bipolar/fisiopatologia , Transtornos do Sono-Vigília/psicologia , Sono , Actigrafia , Adulto , Afeto , Transtorno Bipolar/complicações , Estudos de Casos e Controles , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Polissonografia , Irmãos , Transtornos do Sono-Vigília/genética
15.
Eur Neuropsychopharmacol ; 26(11): 1741-1751, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27665062

RESUMO

There is evidence that brain structure is abnormal in patients with bipolar disorder. Lithium intake appears to ׳normalise׳ global and local brain volumes, but effects of antipsychotic medication on brain volume or cortical thickness are less clear. Here, we aim to disentangle disease-specific brain deviations from those induced by antipsychotic medication and lithium intake using a large homogeneous sample of patients with bipolar disorder type I. Magnetic resonance imaging brain scans were obtained from 266 patients and 171 control subjects. Subcortical volumes and global and focal cortical measures (volume, thickness, and surface area) were compared between patients and controls. In patients, the association between lithium and antipsychotic medication intake and global, subcortical and cortical measures was investigated. Patients showed significantly larger lateral and third ventricles, smaller total brain, caudate nucleus, and pallidum volumes and thinner cortex in some small clusters in frontal, parietal and cingulate regions as compared with controls. Lithium-free patients had significantly smaller total brain, thalamus, putamen, pallidum, hippocampus and accumbens volumes compared to patients on lithium. In patients, use of antipsychotic medication was related to larger third ventricle and smaller hippocampus and supramarginal cortex volume. Patients with bipolar disorder show abnormalities in total brain, subcortical, and ventricle volume, particularly in the nucleus caudate and pallidum. Abnormalities in cortical thickness were scattered and clusters were relatively small. Lithium-free patients showed more pronounced abnormalities as compared with those on lithium. The associations between antipsychotic medication and brain volume are subtle and less pronounced than those of lithium.


Assuntos
Antipsicóticos/uso terapêutico , Transtorno Bipolar/diagnóstico por imagem , Transtorno Bipolar/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Compostos de Lítio/uso terapêutico , Adolescente , Adulto , Fatores Etários , Idoso , Transtorno Bipolar/psicologia , Encéfalo/efeitos dos fármacos , Córtex Cerebral/diagnóstico por imagem , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Testes de Inteligência , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Fatores Sexuais , Adulto Jovem
16.
Nat Commun ; 7: 10967, 2016 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-26997371

RESUMO

DNA methylation likely plays a role in the regulation of human stress reactivity. Here we show that in a genome-wide analysis of blood DNA methylation in 85 healthy individuals, a locus in the Kit ligand gene (KITLG; cg27512205) showed the strongest association with cortisol stress reactivity (P=5.8 × 10(-6)). Replication was obtained in two independent samples using either blood (N=45, P=0.001) or buccal cells (N=255, P=0.004). KITLG methylation strongly mediates the relationship between childhood trauma and cortisol stress reactivity in the discovery sample (32% mediation). Its genomic location, a CpG island shore within an H3K27ac enhancer mark, and the correlation between methylation in the blood and prefrontal cortex provide further evidence that KITLG methylation is functionally relevant for the programming of stress reactivity in the human brain. Our results extend preclinical evidence for epigenetic regulation of stress reactivity to humans and provide leads to enhance our understanding of the neurobiological pathways underlying stress vulnerability.


Assuntos
Metilação de DNA/genética , Genoma Humano , Hidrocortisona/metabolismo , Estresse Psicológico/genética , Ferimentos e Lesões/genética , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Epigênese Genética , Grupos Étnicos/genética , Feminino , Redes Reguladoras de Genes , Loci Gênicos , Estudo de Associação Genômica Ampla , Histonas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Fator de Células-Tronco/genética , Estresse Psicológico/sangue , Ferimentos e Lesões/sangue , Adulto Jovem
17.
Epigenomics ; 8(2): 197-208, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26792232

RESUMO

AIM: In view of the potential effects of psychiatric drugs on DNA methylation, we investigated whether medication use in bipolar disorder is associated with DNA methylation signatures. EXPERIMENTAL PROCEDURES: Blood-based DNA methylation patterns of six frequently used psychotropic drugs (lithium, quetiapine, olanzapine, lamotrigine, carbamazepine, and valproic acid) were examined in 172 bipolar disorder patients. After adjustment for cell type composition, we investigated gene networks, principal components, hypothesis-driven genes and epigenome-wide individual loci. RESULTS: Valproic acid and quetiapine were significantly associated with altered methylation signatures after adjustment for drug-related changes on celltype composition. CONCLUSION: Psychiatric drugs influence DNA methylation patterns over and above cell type composition in bipolar disorder. Drug-related changes in DNA methylation are therefore not only an important confounder in psychiatric epigenetics but may also inform on the biological mechanisms underlying drug efficacy.


Assuntos
Afeto/efeitos dos fármacos , Antipsicóticos/farmacologia , Transtorno Bipolar/genética , Transtorno Bipolar/psicologia , Metilação de DNA , Regulação da Expressão Gênica/efeitos dos fármacos , Transcriptoma , Antipsicóticos/uso terapêutico , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/tratamento farmacológico , Análise por Conglomerados , Biologia Computacional/métodos , Epigênese Genética/efeitos dos fármacos , Epigenômica/métodos , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos
18.
Hum Brain Mapp ; 37(1): 122-34, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26454006

RESUMO

The notion that healthy brain function emerges from coordinated neural activity constrained by the brain's network of anatomical connections--i.e., the connectome--suggests that alterations in the connectome's wiring pattern may underlie brain disorders. Corroborating this hypothesis, studies in schizophrenia are indicative of altered connectome architecture including reduced communication efficiency, disruptions of central brain hubs, and affected "rich club" organization. Whether similar deficits are present in bipolar disorder is currently unknown. This study examines structural connectome topology in 216 bipolar I disorder patients as compared to 144 healthy controls, focusing in particular on central regions (i.e., brain hubs) and connections (i.e., rich club connections, interhemispheric connections) of the brain's network. We find that bipolar I disorder patients exhibit reduced global efficiency (-4.4%, P =0.002) and that this deficit relates (r = 0.56, P < 0.001) to reduced connectivity strength of interhemispheric connections (-13.0%, P = 0.001). Bipolar disorder patients were found not to show predominant alterations in the strength of brain hub connections in general, or of connections spanning brain hubs (i.e., "rich club" connections) in particular (all P > 0.1). These findings highlight a role for aberrant brain network architecture in bipolar I disorder with reduced global efficiency in association with disruptions in interhemispheric connectivity, while the central "rich club" system appears not to be particularly affected.


Assuntos
Transtorno Bipolar/patologia , Encéfalo/patologia , Conectoma , Vias Neurais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtorno Bipolar/fisiopatologia , Mapeamento Encefálico , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Adulto Jovem
19.
Epigenomics ; 7(4): 593-608, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26111031

RESUMO

Animal studies have identified persistent and functional effects of traumatic stress on the epigenome. This review discusses the clinical evidence for trauma-induced changes in DNA methylation across the life span in humans. Studies are reviewed based on reports of trauma exposure during the prenatal period (13 studies), early life (20 studies), and adulthood (ten studies). Even though it is apparent that traumatic stress influences the human epigenome, there are significant drawbacks in the existing human literature. These include a lack of longitudinal studies, methodological heterogeneity, selection of tissue type, and the influence of developmental stage and trauma type on methylation outcomes. These issues are discussed in order to present a way in which future studies can gain more insight into the functional relevance of trauma-related DNA methylation changes. Epigenetic studies investigating the detrimental effects of traumatic stress have great potential for an improved detection and treatment of trauma-related psychiatric disorders.


Assuntos
Metilação de DNA , Epigênese Genética , Transtornos de Estresse Traumático/genética , Animais , Sequência de Bases , Humanos , Dados de Sequência Molecular
20.
Psychoneuroendocrinology ; 54: 90-102, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25686805

RESUMO

The MR is an important regulator of the hypothalamic-pituitary-adrenal (HPA) axis and a prime target for corticosteroids. There is increasing evidence from both clinical and preclinical studies that the MR has different effects on behavior and mood in males and females. To investigate the hypothesis that the MR sex-dependently influences the relation between childhood maltreatment and depression, we investigated three common and functional MR haplotypes (GA, CA, and CG haplotype, based on rs5522 and rs2070951) in a population-based cohort (N = 665) and an independent clinical cohort from the Netherlands Study of Depression and Anxiety (NESDA) (N = 1639). The CA haplotype sex-dependently moderated the relation between childhood maltreatment and depressive symptoms both in the population-based sample (sex × maltreatment × haplotype: ß = -4.07, P = 0.029) and in the clinical sample (sex × maltreatment × haplotype, ß = -2.40, P = 0.011). Specifically, female individuals in the population-based sample were protected (ß = -4.58, P = 2.0 e(-5)), whereas males in the clinical sample were at increased risk (ß = 2.54, P = 0.0022). In line with these results, female GA haplotype carriers displayed increased vulnerability in the population-based sample (ß = 4.58, P = 7.5 e(-5)) whereas male CG-carriers showed increased resilience in the clinical sample (ß = -2.71, P = 0.016). Consistently, we found a decreased lifetime MDD risk for male GA haplotype carriers following childhood maltreatment but an increased risk for male CA haplotype carriers in the clinical sample. In both samples, sex-dependent effects were observed for GA-GA diplotype carriers. In summary, sex plays an important role in determining whether functional genetic variation in MR is beneficial or detrimental, with an apparent female advantage for the CA haplotype but male advantage for the GA and CG haplotype. These sex-dependent effects of MR on depression susceptibility following childhood maltreatment are relevant in light of the increased prevalence of mood disorders in women and point to a sex-specific role of MR in the etiology of depression following childhood maltreatment.


Assuntos
Maus-Tratos Infantis , Depressão/genética , Receptores de Mineralocorticoides/genética , Adolescente , Adulto , Suscetibilidade a Doenças , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores Sexuais , Adulto Jovem
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