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1.
Transl Psychiatry ; 9(1): 219, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488809

RESUMO

Trials testing the effect of vitamin D or omega-3 polyunsaturated fatty acid (n3-PUFA) supplementation on major depressive disorder (MDD) reported conflicting findings. These trials were inspired by epidemiological evidence suggesting an inverse association of circulating 25-hydroxyvitamin D (25-OH-D) and n3-PUFA levels with MDD. Observational associations may emerge from unresolved confounding, shared genetic risk, or direct causal relationships. We explored the nature of these associations exploiting data and statistical tools from genomics. Results from genome-wide association studies on 25-OH-D (N = 79 366), n3-PUFA (N = 24 925), and MDD (135 458 cases, 344 901 controls) were applied to individual-level data (>2000 subjects with measures of genotype, DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) lifetime MDD diagnoses and circulating 25-OH-D and n3-PUFA) and summary-level data analyses. Shared genetic risk between traits was tested by polygenic risk scores (PRS). Two-sample Mendelian Randomization (2SMR) analyses tested the potential bidirectional causality between traits. In individual-level data analyses, PRS were associated with the phenotype of the same trait (PRS 25-OH-D p = 1.4e - 20, PRS n3-PUFA p = 9.3e - 6, PRS MDD p = 1.4e - 4), but not with the other phenotypes, suggesting a lack of shared genetic effects. In summary-level data analyses, 2SMR analyses provided no evidence of a causal role on MDD of 25-OH-D (p = 0.50) or n3-PUFA (p = 0.16), or for a causal role of MDD on 25-OH-D (p = 0.25) or n3-PUFA (p = 0.66). Applying genomics tools indicated that shared genetic risk or direct causality between 25-OH-D, n3-PUFA, and MDD is unlikely: unresolved confounding may explain the associations reported in observational studies. These findings represent a cautionary tale for testing supplementation of these compounds in preventing or treating MDD.

2.
Nat Rev Genet ; 20(10): 567-581, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31171865

RESUMO

The genetic correlation describes the genetic relationship between two traits and can contribute to a better understanding of the shared biological pathways and/or the causality relationships between them. The rarity of large family cohorts with recorded instances of two traits, particularly disease traits, has made it difficult to estimate genetic correlations using traditional epidemiological approaches. However, advances in genomic methodologies, such as genome-wide association studies, and widespread sharing of data now allow genetic correlations to be estimated for virtually any trait pair. Here, we review the definition, estimation, interpretation and uses of genetic correlations, with a focus on applications to human disease.

3.
Am J Med Genet B Neuropsychiatr Genet ; 180(6): 439-447, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30708398

RESUMO

Major depressive disorder (MDD) is clinically heterogeneous with prevalence rates twice as high in women as in men. There are many possible sources of heterogeneity in MDD most of which are not measured in a sufficiently comparable way across study samples. Here, we assess genetic heterogeneity based on two fundamental measures, between-cohort and between-sex heterogeneity. First, we used genome-wide association study (GWAS) summary statistics to investigate between-cohort genetic heterogeneity using the 29 research cohorts of the Psychiatric Genomics Consortium (PGC; N cases = 16,823, N controls = 25,632) and found that some of the cohort heterogeneity can be attributed to ascertainment differences (such as recruitment of cases from hospital vs. community sources). Second, we evaluated between-sex genetic heterogeneity using GWAS summary statistics from the PGC, Kaiser Permanente GERA, UK Biobank, and the Danish iPSYCH studies but did not find convincing evidence for genetic differences between the sexes. We conclude that there is no evidence that the heterogeneity between MDD data sets and between sexes reflects genetic heterogeneity. Larger sample sizes with detailed phenotypic records and genomic data remain the key to overcome heterogeneity inherent in assessment of MDD.

4.
Am J Med Genet B Neuropsychiatr Genet ; 177(1): 40-49, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29159863

RESUMO

Gene by environment (GxE) interaction studies have investigated the influence of a number of candidate genes and variants for major depressive disorder (MDD) on the association between childhood trauma and MDD. Most of these studies are hypothesis driven and investigate only a limited number of SNPs in relevant pathways using differing methodological approaches. Here (1) we identified 27 genes and 268 SNPs previously associated with MDD or with GxE interaction in MDD and (2) analyzed their impact on GxE in MDD using a common approach in 3944 subjects of European ancestry from the Psychiatric Genomics Consortium who had completed the Childhood Trauma Questionnaire. (3) We subsequently used the genome-wide SNP data for a genome-wide case-control GxE model and GxE case-only analyses testing for an enrichment of associated SNPs. No genome-wide significant hits and no consistency among the signals of the different analytic approaches could be observed. This is the largest study for systematic GxE interaction analysis in MDD in subjects of European ancestry to date. Most of the known candidate genes/variants could not be supported. Thus, their impact on GxE interaction in MDD may be questionable. Our results underscore the need for larger samples, more extensive assessment of environmental exposures, and greater efforts to investigate new methodological approaches in GxE models for MDD.


Assuntos
Depressão/genética , Transtorno Depressivo Maior/genética , Estudos de Casos e Controles , Depressão/etiologia , Transtorno Depressivo Maior/etiologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Acontecimentos que Mudam a Vida , Masculino , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
5.
Biol Psychiatry ; 2017 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-29129318

RESUMO

BACKGROUND: The heterogeneity of genetic effects on major depressive disorder (MDD) may be partly attributable to moderation of genetic effects by environment, such as exposure to childhood trauma (CT). Indeed, previous findings in two independent cohorts showed evidence for interaction between polygenic risk scores (PRSs) and CT, albeit in opposing directions. This study aims to meta-analyze MDD-PRS × CT interaction results across these two and other cohorts, while applying more accurate PRSs based on a larger discovery sample. METHODS: Data were combined from 3024 MDD cases and 2741 control subjects from nine cohorts contributing to the MDD Working Group of the Psychiatric Genomics Consortium. MDD-PRS were based on a discovery sample of ∼110,000 independent individuals. CT was assessed as exposure to sexual or physical abuse during childhood. In a subset of 1957 cases and 2002 control subjects, a more detailed five-domain measure additionally included emotional abuse, physical neglect, and emotional neglect. RESULTS: MDD was associated with the MDD-PRS (odds ratio [OR] = 1.24, p = 3.6 × 10-5, R2 = 1.18%) and with CT (OR = 2.63, p = 3.5 × 10-18 and OR = 2.62, p = 1.4 ×10-5 for the two- and five-domain measures, respectively). No interaction was found between MDD-PRS and the two-domain and five-domain CT measure (OR = 1.00, p = .89 and OR = 1.05, p = .66). CONCLUSIONS: No meta-analytic evidence for interaction between MDD-PRS and CT was found. This suggests that the previously reported interaction effects, although both statistically significant, can best be interpreted as chance findings. Further research is required, but this study suggests that the genetic heterogeneity of MDD is not attributable to genome-wide moderation of genetic effects by CT.

6.
JAMA Psychiatry ; 74(12): 1214-1225, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29049554

RESUMO

Importance: The association between major depressive disorder (MDD) and obesity may stem from shared immunometabolic mechanisms particularly evident in MDD with atypical features, characterized by increased appetite and/or weight (A/W) during an active episode. Objective: To determine whether subgroups of patients with MDD stratified according to the A/W criterion had a different degree of genetic overlap with obesity-related traits (body mass index [BMI] and levels of C-reactive protein [CRP] and leptin). Design, Setting, and Patients: This multicenter study assembled genome-wide genotypic and phenotypic measures from 14 data sets of the Psychiatric Genomics Consortium. Data sets were drawn from case-control, cohort, and population-based studies, including 26 628 participants with established psychiatric diagnoses and genome-wide genotype data. Data on BMI were available for 15 237 participants. Data were retrieved and analyzed from September 28, 2015, through May 20, 2017. Main Outcomes and Measures: Lifetime DSM-IV MDD was diagnosed using structured diagnostic instruments. Patients with MDD were stratified into subgroups according to change in the DSM-IV A/W symptoms as decreased or increased. Results: Data included 11 837 participants with MDD and 14 791 control individuals, for a total of 26 628 participants (59.1% female and 40.9% male). Among participants with MDD, 5347 (45.2%) were classified in the decreased A/W and 1871 (15.8%) in the increased A/W subgroups. Common genetic variants explained approximately 10% of the heritability in the 2 subgroups. The increased A/W subgroup showed a strong and positive genetic correlation (SE) with BMI (0.53 [0.15]; P = 6.3 × 10-4), whereas the decreased A/W subgroup showed an inverse correlation (-0.28 [0.14]; P = .06). Furthermore, the decreased A/W subgroup had a higher polygenic risk for increased BMI (odds ratio [OR], 1.18; 95% CI, 1.12-1.25; P = 1.6 × 10-10) and levels of CRP (OR, 1.08; 95% CI, 1.02-1.13; P = 7.3 × 10-3) and leptin (OR, 1.09; 95% CI, 1.06-1.12; P = 1.7 × 10-3). Conclusions and Relevance: The phenotypic associations between atypical depressive symptoms and obesity-related traits may arise from shared pathophysiologic mechanisms in patients with MDD. Development of treatments effectively targeting immunometabolic dysregulations may benefit patients with depression and obesity, both syndromes with important disability.


Assuntos
Fissura , Transtorno Depressivo Maior , Obesidade , Ganho de Peso , Adulto , Índice de Massa Corporal , Proteína C-Reativa/análise , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/imunologia , Transtorno Depressivo Maior/metabolismo , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Cooperação Internacional , Masculino , Obesidade/diagnóstico , Obesidade/genética , Obesidade/psicologia , Escalas de Graduação Psiquiátrica
8.
PLoS Genet ; 13(4): e1006528, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28448500

RESUMO

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.


Assuntos
Adiposidade/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Exercício , Obesidade/genética , Adiposidade/fisiologia , Índice de Massa Corporal , Epigenômica , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Obesidade/fisiopatologia , Circunferência da Cintura , Relação Cintura-Quadril
9.
Biol Psychiatry ; 81(4): 316-324, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-27576130

RESUMO

BACKGROUND: Limited successes of gene finding for major depressive disorder (MDD) may be partly due to phenotypic heterogeneity. We tested whether the genetic load for MDD, bipolar disorder, and schizophrenia (SCZ) is increased in phenotypically more homogenous MDD patients identified by specific clinical characteristics. METHODS: Patients (n = 1539) with a DSM-IV MDD diagnosis and control subjects (n = 1792) were from two large cohort studies (Netherlands Study of Depression and Anxiety and Netherlands Twin Register). Genomic profile risk scores (GPRSs) for MDD, bipolar disorder, and SCZ were based on meta-analysis results of the Psychiatric Genomics Consortium. Regression analyses (adjusted for year of birth, sex, three principal components) examined the association between GPRSs with characteristics and GPRSs with MDD subgroups stratified according to the most relevant characteristics. The proportion of liability variance explained by GPRSs for each MDD subgroup was estimated. RESULTS: GPRS-MDD explained 1.0% (p = 4.19e-09) of MDD variance, and 1.5% (p = 4.23e-09) for MDD endorsing nine DSM symptoms. GPRS-bipolar disorder explained 0.6% (p = 2.97e-05) of MDD variance and 1.1% (p = 1.30e-05) for MDD with age at onset <18 years. GPRS-SCZ explained 2.0% (p = 6.15e-16) of MDD variance, 2.6% (p = 2.88e-10) for MDD with higher symptom severity, and 2.3% (p = 2.26e-13) for MDD endorsing nine DSM symptoms. An independent sample replicated the same pattern of stronger associations between cases with more DSM symptoms, as compared to overall MDD, and GPRS-SCZ. CONCLUSIONS: MDD patients with early age at onset and higher symptom severity have an increased genetic risk for three major psychiatric disorders, suggesting that it is useful to create phenotypically more homogenous groups when searching for genes associated with MDD.


Assuntos
Transtorno Bipolar/genética , Transtorno Depressivo Maior/genética , Carga Genética , Predisposição Genética para Doença , Esquizofrenia/genética , Adulto , Idade de Início , Transtorno Bipolar/diagnóstico , Transtorno Depressivo Maior/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Escalas de Graduação Psiquiátrica , Fatores de Risco , Esquizofrenia/diagnóstico
10.
JAMA Psychiatry ; 73(11): 1189-1195, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27732705

RESUMO

Importance: Considerable partner resemblances have been found for a wide range of psychiatric disorders, meaning that partners of affected individuals have an increased risk of being affected compared with partners of unaffected individuals. If this resemblance is reflected in genetic similarity between partners, genetic risk is anticipated to accumulate in offspring, but these potential consequences have not been quantified and have been left implicit. Observations: The anticipated consequences of partner resemblance on prevalence and heritability of psychiatric traits in the offspring generation were modeled for disorders with varying heritabilities, population prevalence (lifetime risk), and magnitudes of partner resemblance. These models facilitate interpretation for a wide range of psychiatric disorders, such as autism, schizophrenia, and depression. The genetic consequences of partner resemblance are most pronounced when attributable to phenotypic assortment (driven by the psychiatric trait). Phenotypic assortment results in increased genetic variance in the offspring generation, which may result in increased heritability and population prevalence. These consequences add generation after generation to a limit, but assortative mating is unlikely to balance the impact of reduced fecundity of patients with psychiatric disorders in the long term. This modeling suggests that the heritabilities of psychiatric disorders are unlikely to increase by more than 5% from 1 generation of assortative mating (maximally 13% across multiple generations). The population prevalence will increase most for less common disorders with high heritability; for example, the prevalence of autism might increase by 1.5-fold after 1 generation of assortative mating (≥2.4-fold in the long term) depending on several assumptions. Conclusions and Relevance: The considerable partner resemblances found for psychiatric disorders deserve more detailed interpretation than has been provided thus far. Although the limitations of modeling are emphasized, the anticipated consequences are at most modest for the heritability but may be considerable for the population prevalence of rare disorders with a high heritability.


Assuntos
Casamento , Transtornos Mentais/genética , Modelos Genéticos , Fenótipo , Comportamento Reprodutivo , Seleção Genética/genética , Estudos Transversais , Feminino , Genética Populacional , Genótipo , Humanos , Masculino , Casamento/psicologia , Transtornos Mentais/epidemiologia , Comportamento Reprodutivo/psicologia , Risco , Estatística como Assunto
11.
Nat Genet ; 48(7): 718-24, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27213288

RESUMO

The offspring of older fathers have higher risk of psychiatric disorders such as schizophrenia and autism. Paternal-age-related de novo mutations are widely assumed to be the underlying causal mechanism, and, although such mutations must logically make some contribution, there are alternative explanations (for example, elevated liability to psychiatric illness may delay fatherhood). We used population genetic models based on empirical observations of key parameters (for example, mutation rate, prevalence, and heritability) to assess the genetic relationship between paternal age and risk of psychiatric illness. These models suggest that age-related mutations are unlikely to explain much of the increased risk of psychiatric disorders in children of older fathers. Conversely, a model incorporating a weak correlation between age at first child and liability to psychiatric illness matched epidemiological observations. Our results suggest that genetic risk factors shared by older fathers and their offspring are a credible alternative explanation to de novo mutations for risk to children of older fathers.


Assuntos
Transtorno Autístico/etiologia , Marcadores Genéticos/genética , Mutação/genética , Idade Paterna , Esquizofrenia/etiologia , Fatores Etários , Criança , Humanos , Masculino , Fatores de Risco
12.
Am J Hum Genet ; 98(2): 382-91, 2016 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-26849113

RESUMO

Genome-wide association studies (GWASs) are an optimal design for discovery of disease risk loci for diseases whose underlying genetic architecture includes many common causal loci of small effect (a polygenic architecture). We consider two designs that deserve careful consideration if the true underlying genetic architecture of the trait is polygenic: parent-offspring trios and unscreened control subjects. We assess these designs in terms of quantification of the total contribution of genome-wide genetic markers to disease risk (SNP heritability) and power to detect an associated risk allele. First, we show that trio designs should be avoided when: (1) the disease has a lifetime risk > 1%; (2) trio probands are ascertained from families with more than one affected sibling under which scenario the SNP heritability can drop by more than 50% and power can drop as much as from 0.9 to 0.15 for a sample of 20,000 subjects; or (3) assortative mating occurs (spouse correlation of the underlying liability to the disorder), which decreases the SNP heritability but not the power to detect a single locus in the trio design. Some studies use unscreened rather than screened control subjects because these can be easier to collect; we show that the estimated SNP heritability should then be scaled by dividing by (1 - K × u)(2) for disorders with population prevalence K and proportion of unscreened control subjects u. When omitting to scale appropriately, the SNP heritability of, for example, major depressive disorder (K = 0.15) would be underestimated by 28% when none of the control subjects are screened.


Assuntos
Estudos de Associação Genética/métodos , Alelos , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/genética , Frequência do Gene , Loci Gênicos , Marcadores Genéticos , Predisposição Genética para Doença , Fenótipo , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável
13.
Psychoneuroendocrinology ; 55: 154-63, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25765757

RESUMO

OBJECTIVE: Previous research found that variants of the glucocorticoid receptor (GR) (9ß, ER22/23EK, BclI, TthIIIl, NR3C1-1 and N363S) and mineralocorticoid receptor (MR) gene polymorphism (-2 C/G and I180V) are associated with both glucocorticoid (GC) sensitivity and major depressive disorder (MDD). There are no data which investigated prospectively whether these variants are associated with recurrence of MDD. METHODS: Data were derived from the Netherlands Study of Depression and Anxiety (NESDA) which used the Composite International Diagnostic Interview (CIDI) to determine MDD. Polymorphisms in the GR and MR gene were determined and haplotypes were characterized. We analyzed in retrospect whether recurrent MDD (n=951) in comparison with first onset MDD (n=919) was associated with polymorphisms in the GR and MR gene. Furthermore, we analyzed prospectively for 4 years the time to recurrence among 683 subjects with a remitted MDD diagnosis. Time to recurrence of MDD was assessed using the CIDI and a life chart interview. Additionally, we analyzed interactions of the investigated polymorphisms with childhood trauma and recent negative life events. RESULTS: GR and MR gene polymorphisms and derived haplotypes were not associated with recurrence of depression in both retrospective and prospective analyses. In addition, no consistent interactions between GR and MR polymorphisms and childhood trauma or life events were found. CONCLUSION: This study did not find consistent associations between GR and MR gene polymorphisms, interactions between GR and MR haplotypes and stressful conditions and recurrence of MDD.


Assuntos
Transtorno Depressivo Maior/genética , Receptores de Glucocorticoides/genética , Receptores de Mineralocorticoides/genética , Adolescente , Adulto , Adultos Sobreviventes de Eventos Adversos na Infância/psicologia , Idoso , Estudos de Coortes , Transtorno Depressivo Maior/psicologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Recidiva , Estresse Psicológico/genética , Estresse Psicológico/psicologia , Adulto Jovem
14.
Br J Psychiatry ; 205(2): 113-9, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24925986

RESUMO

BACKGROUND: Research on gene × environment interaction in major depressive disorder (MDD) has thus far primarily focused on candidate genes, although genetic effects are known to be polygenic. AIMS: To test whether the effect of polygenic risk scores on MDD is moderated by childhood trauma. METHOD: The study sample consisted of 1645 participants with a DSM-IV diagnosis of MDD and 340 screened controls from The Netherlands. Chronic or remitted episodes (severe MDD) were present in 956 participants. The occurrence of childhood trauma was assessed with the Childhood Trauma Interview and the polygenic risk scores were based on genome-wide meta-analysis results from the Psychiatric Genomics Consortium. RESULTS: The polygenic risk scores and childhood trauma independently affected MDD risk, and evidence was found for interaction as departure from both multiplicativity and additivity, indicating that the effect of polygenic risk scores on depression is increased in the presence of childhood trauma. The interaction effects were similar in predicting all MDD risk and severe MDD risk, and explained a proportion of variation in MDD risk comparable to the polygenic risk scores themselves. CONCLUSIONS: The interaction effect found between polygenic risk scores and childhood trauma implies that (1) studies on direct genetic effect on MDD gain power by focusing on individuals exposed to childhood trauma, and that (2) individuals with both high polygenic risk scores and exposure to childhood trauma are particularly at risk for developing MDD.


Assuntos
Sobreviventes Adultos de Maus-Tratos Infantis/estatística & dados numéricos , Maus-Tratos Infantis/estatística & dados numéricos , Transtorno Depressivo Maior/epidemiologia , Adulto , Estudos de Casos e Controles , Criança , Transtorno Depressivo Maior/genética , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Medição de Risco , Fatores de Risco
15.
Br J Psychiatry ; 203(2): 132-9, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23787062

RESUMO

BACKGROUND: Thus far collaborative stepped care (CSC) studies have not incorporated self-help as a first step. AIMS: To evaluate the effectiveness of CSC in the treatment of common mental disorders. METHOD: An 8-month cluster randomised controlled trial comparing CSC to care as usual (CAU) (Dutch Trial Register identifier NTR1224). The CSC consisted of a stepped care approach guided by a psychiatric nurse in primary care with the addition of antidepressants dependent on the severity of the disorder, followed by cognitive-behavioural therapy in mental healthcare. RESULTS: Twenty general practitioners (GPs) and 8 psychiatric nurses were randomised to provide CSC or CAU. The GPs recruited 163 patients of whom 85% completed the post-test measurements. At 4-month mid-test CSC was superior to CAU: 74.7% (n = 68) v. 50.8% (n = 31) responders (P = 0.003). At 8-month post-test and 12-month follow-up no significant differences were found as the patients in the CAU group improved as well. CONCLUSIONS: Treatment within a CSC model resulted in an earlier treatment response compared with CAU.


Assuntos
Transtornos de Ansiedade/terapia , Terapia Cognitivo-Comportamental/métodos , Transtorno Depressivo/terapia , Equipe de Assistência ao Paciente , Autocuidado , Adulto , Transtornos de Ansiedade/psicologia , Transtorno Depressivo/psicologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Atenção Primária à Saúde , Resultado do Tratamento
16.
J Affect Disord ; 146(1): 91-9, 2013 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-23021380

RESUMO

BACKGROUND: There is ongoing interest in the possible interaction of the serotonin-transporter-linked polymorphic region (5-HTTLPR) with environmental factors in determining Major Depressive Disorder (MDD). The current study contributes to this research area by comprehensively examining the interaction-effects and direct-effects of 5-HTTLPR and five environmental factors on MDD prevalence and course in a well-characterized longitudinal sample. METHODS: The sample consisted of 1625 patients with a CIDI-confirmed diagnosis of MDD and 1698 screened controls from the Netherlands. Four MDD outcomes were studied as dependent variables: one main MDD prevalence-outcome (all MDD), two more severe MDD prevalence-outcomes (suicidal and chronic MDD), and one MDD course outcome (chronic versus non-chronic MDD). Because SNP rs25531 modifies the effect of 5-HTTLPR, haplotypes of 5-HTTLPR and rs25531 were measured. For the four MDD outcome measures, we examined the direct effects of 5-HTTLPR/rs25531-haplotypes, five environmental factors (lifetime and recent stressful life-events, sexual abuse, low educational attainment, and childhood trauma) and their interaction in logistic regression models. RESULTS: The environmental factors had large and consistent effects on all four MDD outcomes, including course of MDD. The 5-HTTLPR/rs25531-haplotype had a suggestive effect on course of MDD, but not on presence of MDD. Gene-by-environment interaction was significant (<0.05) for one of the 20 tests performed, which is not more than expected by chance. LIMITATIONS: Environmental factors were not assessed before the onset of MDD. CONCLUSIONS: Environmental factors had a strong impact on the presence and course of MDD, but no evidence for gene-by-environment interaction was found.


Assuntos
Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Interação Gene-Ambiente , Acontecimentos que Mudam a Vida , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adulto , Sobreviventes Adultos de Maus-Tratos Infantis/psicologia , Estudos de Casos e Controles , Escolaridade , Feminino , Haplótipos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Polimorfismo de Nucleotídeo Único , Prevalência , Fatores de Risco , Delitos Sexuais/psicologia
17.
Cell Oncol (Dordr) ; 35(3): 181-8, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22581446

RESUMO

BACKGROUND: Because of the distinct clinical presentation of early and advanced stage ovarian cancer, we aim to clarify whether these disease entities are solely separated by time of diagnosis or whether they arise from distinct molecular events. METHODS: Sixteen early and sixteen advanced stage ovarian carcinomas, matched for histological subtype and differentiation grade, were included. Genomic aberrations were compared for each early and advanced stage ovarian cancer by array comparative genomic hybridization. To study how the aberrations correlate to the clinical characteristics of the tumors we clustered tumors based on the genomic aberrations. RESULTS: The genomic aberration patterns in advanced stage cancer equalled those in early stage, but were more frequent in advanced stage (p = 0.012). Unsupervised clustering based on genomic aberrations yielded two clusters that significantly discriminated early from advanced stage (p = 0.001), and that did differ significantly in survival (p = 0.002). These clusters however did give a more accurate prognosis than histological subtype or differentiation grade. CONCLUSION: This study indicates that advanced stage ovarian cancer either progresses from early stage or from a common precursor lesion but that they do not arise from distinct carcinogenic molecular events. Furthermore, we show that array comparative genomic hybridization has the potential to identify clinically distinct patients.


Assuntos
Aberrações Cromossômicas , Genoma Humano/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise por Conglomerados , Hibridização Genômica Comparativa , Intervalo Livre de Doença , Feminino , Dosagem de Genes/genética , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Estadiamento de Neoplasias
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