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1.
Twin Res Hum Genet ; : 1-7, 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31708010

RESUMO

Meta-analyses suggest that clinical psychopathology is preceded by dimensional behavioral and cognitive phenotypes such as psychotic experiences, executive functioning, working memory and affective dysregulation that are determined by the interplay between genetic and nongenetic factors contributing to the severity of psychopathology. The liability to mental ill health can be psychometrically measured using experimental paradigms that assess neurocognitive processes such as salience attribution, sensitivity to social defeat and reward sensitivity. Here, we describe the TwinssCan, a longitudinal general population twin cohort, which comprises 1202 individuals (796 adolescent/young adult twins, 43 siblings and 363 parents) at baseline. The TwinssCan is part of the European Network of National Networks studying Gene-Environment Interactions in Schizophrenia project and recruited from the East Flanders Prospective Twin Survey. The main objective of this project is to understand psychopathology by evaluating the contribution of genetic and nongenetic factors on subclinical expressions of dimensional phenotypes at a young age before the onset of disorder and their association with neurocognitive processes, such as salience attribution, sensitivity to social defeat and reward sensitivity.

2.
Front Psychiatry ; 10: 676, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31607966

RESUMO

Introduction: White noise speech illusions index liability for psychotic disorder in case-control comparisons. In the current study, we examined i) the rate of white noise speech illusions in siblings of patients with psychotic disorder and ii) to what degree this rate would be contingent on exposure to known environmental risk factors (childhood adversity and recent life events) and level of known endophenotypic dimensions of psychotic disorder [psychotic experiences assessed with the Community Assessment of Psychic Experiences (CAPE) scale and cognitive ability]. Methods: The white noise task was used as an experimental paradigm to elicit and measure speech illusions in 1,014 patients with psychotic disorders, 1,157 siblings, and 1,507 healthy participants. We examined associations between speech illusions and increasing familial risk (control -> sibling -> patient), modeled as both a linear and a categorical effect, and associations between speech illusions and level of childhood adversities and life events as well as with CAPE scores and cognitive ability scores. Results: While a positive association was found between white noise speech illusions across hypothesized increasing levels of familial risk (controls -> siblings -> patients) [odds ratio (OR) linear 1.11, 95% confidence interval (CI) 1.02-1.21, p = 0.019], there was no evidence for a categorical association with sibling status (OR 0.93, 95% CI 0.79-1.09, p = 0.360). The association between speech illusions and linear familial risk was greater if scores on the CAPE positive scale were higher (p interaction = 0.003; ORlow CAPE positive scale 0.96, 95% CI 0.85-1.07; ORhigh CAPE positive scale 1.26, 95% CI 1.09-1.46); cognitive ability was lower (p interaction < 0.001; ORhigh cognitive ability 0.94, 95% CI 0.84-1.05; ORlow cognitive ability 1.43, 95% CI 1.23-1.68); and exposure to childhood adversity was higher (p interaction < 0.001; ORlow adversity 0.92, 95% CI 0.82-1.04; ORhigh adversity 1.31, 95% CI 1.13-1.52). A similar, although less marked, pattern was seen for categorical patient-control and sibling-control comparisons. Exposure to recent life events did not modify the association between white noise and familial risk (p interaction = 0.232). Conclusion: The association between white noise speech illusions and familial risk is contingent on additional evidence of endophenotypic expression and of exposure to childhood adversity. Therefore, speech illusions may represent a trait-dependent risk marker.

3.
Schizophr Bull ; 45(5): 960-965, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31508804

RESUMO

Exposures constitute a dense network of the environment: exposome. Here, we argue for embracing the exposome paradigm to investigate the sum of nongenetic "risk" and show how predictive modeling approaches can be used to construct an exposome score (ES; an aggregated score of exposures) for schizophrenia. The training dataset consisted of patients with schizophrenia and controls, whereas the independent validation dataset consisted of patients, their unaffected siblings, and controls. Binary exposures were cannabis use, hearing impairment, winter birth, bullying, and emotional, physical, and sexual abuse along with physical and emotional neglect. We applied logistic regression (LR), Gaussian Naive Bayes (GNB), the least absolute shrinkage and selection operator (LASSO), and Ridge penalized classification models to the training dataset. ESs, the sum of weighted exposures based on coefficients from each model, were calculated in the validation dataset. In addition, we estimated ES based on meta-analyses and a simple sum score of exposures. Accuracy, sensitivity, specificity, area under the receiver operating characteristic, and Nagelkerke's R2 were compared. The ESMeta-analyses performed the worst, whereas the sum score and the ESGNB were worse than the ESLR that performed similar to the ESLASSO and ESRIDGE. The ESLR distinguished patients from controls (odds ratio [OR] = 1.94, P < .001), patients from siblings (OR = 1.58, P < .001), and siblings from controls (OR = 1.21, P = .001). An increase in ESLR was associated with a gradient increase of schizophrenia risk. In reference to the remaining fractions, the ESLR at top 30%, 20%, and 10% of the control distribution yielded ORs of 3.72, 3.74, and 4.77, respectively. Our findings demonstrate that predictive modeling approaches can be harnessed to evaluate the exposome.

4.
Psychol Med ; : 1-14, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31414981

RESUMO

BACKGROUND: First-degree relatives of patients with psychotic disorder have higher levels of polygenic risk (PRS) for schizophrenia and higher levels of intermediate phenotypes. METHODS: We conducted, using two different samples for discovery (n = 336 controls and 649 siblings of patients with psychotic disorder) and replication (n = 1208 controls and 1106 siblings), an analysis of association between PRS on the one hand and psychopathological and cognitive intermediate phenotypes of schizophrenia on the other in a sample at average genetic risk (healthy controls) and a sample at higher than average risk (healthy siblings of patients). Two subthreshold psychosis phenotypes, as well as a standardised measure of cognitive ability, based on a short version of the WAIS-III short form, were used. In addition, a measure of jumping to conclusion bias (replication sample only) was tested for association with PRS. RESULTS: In both discovery and replication sample, evidence for an association between PRS and subthreshold psychosis phenotypes was observed in the relatives of patients, whereas in the controls no association was observed. Jumping to conclusion bias was similarly only associated with PRS in the sibling group. Cognitive ability was weakly negatively and non-significantly associated with PRS in both the sibling and the control group. CONCLUSIONS: The degree of endophenotypic expression of schizophrenia polygenic risk depends on having a sibling with psychotic disorder, suggestive of underlying gene-environment interaction. Cognitive biases may better index genetic risk of disorder than traditional measures of neurocognition, which instead may reflect the population distribution of cognitive ability impacting the prognosis of psychotic disorder.

5.
World Psychiatry ; 18(2): 173-182, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059627

RESUMO

Schizophrenia is a heritable complex phenotype associated with a background risk involving multiple common genetic variants of small effect and a multitude of environmental exposures. Early twin and family studies using proxy-genetic liability measures suggest gene-environment interaction in the etiology of schizophrenia spectrum disorders, but the molecular evidence is scarce. Here, by analyzing the main and joint associations of polygenic risk score for schizophrenia (PRS-SCZ) and environmental exposures in 1,699 patients with a diagnosis of schizophrenia spectrum disorders and 1,542 unrelated controls with no lifetime history of a diagnosis of those disorders, we provide further evidence for gene-environment interaction in schizophrenia. Evidence was found for additive interaction of molecular genetic risk state for schizophrenia (binary mode of PRS-SCZ above 75% of the control distribution) with the presence of lifetime regular cannabis use and exposure to early-life adversities (sexual abuse, emotional abuse, emotional neglect, and bullying), but not with the presence of hearing impairment, season of birth (winter birth), and exposure to physical abuse or physical neglect in childhood. The sensitivity analyses replacing the a priori PRS-SCZ at 75% with alternative cut-points (50% and 25%) confirmed the additive interaction. Our results suggest that the etiopathogenesis of schizophrenia involves genetic underpinnings that act by making individuals more sensitive to the effects of some environmental exposures.

6.
Psychol Med ; 49(11): 1879-1889, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30284529

RESUMO

BACKGROUND: Evidence suggests that cannabis use, childhood adversity, and urbanicity, in interaction with proxy measures of genetic risk, may facilitate onset of psychosis in the sense of early affective dysregulation becoming 'complicated' by, first, attenuated psychosis and, eventually, full-blown psychotic symptoms. METHODS: Data were derived from three waves of the second Netherlands Mental Health Survey and Incidence Study (NEMESIS-2). The impact of environmental risk factors (cannabis use, childhood adversity, and urbanicity) was analyzed across severity levels of psychopathology defined by the degree to which affective dysregulation was 'complicated' by low-grade psychotic experiences ('attenuated psychosis' - moderately severe) and, overt psychotic symptoms leading to help-seeking ('clinical psychosis' - most severe). Familial and non-familial strata were defined based on family history of (mostly) affective disorder and used as a proxy for genetic risk in models of family history × environmental risk interaction. RESULTS: In proxy gene-environment interaction analysis, childhood adversity and cannabis use, and to a lesser extent urbanicity, displayed greater-than-additive risk if there was also evidence of familial affective liability. In addition, the interaction contrast ratio grew progressively greater across severity levels of psychosis admixture (none, attenuated psychosis, clinical psychosis) complicating affective dysregulation. CONCLUSION: Known environmental risks interact with familial evidence of affective liability in driving the level of psychosis admixture in states of early affective dysregulation in the general population, constituting an affective pathway to psychosis. There is interest in decomposing family history of affective liability into the environmental and genetic components that underlie the interactions as shown here.

7.
Psychol Med ; 49(11): 1799-1809, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30160228

RESUMO

BACKGROUND: The jumping to conclusions (JTC) reasoning bias and decreased working memory performance (WMP) are associated with psychosis, but associations with affective disturbances (i.e. depression, anxiety, mania) remain inconclusive. Recent findings also suggest a transdiagnostic phenotype of co-occurring affective disturbances and psychotic experiences (PEs). This study investigated whether JTC bias and decreased WMP are associated with co-occurring affective disturbances and PEs. METHODS: Data were derived from the second Netherlands Mental Health Survey and Incidence Study (NEMESIS-2). Trained interviewers administered the Composite International Diagnostic Interview (CIDI) at three time points in a general population sample (N = 4618). The beads and digit-span task were completed to assess JTC bias and WMP, respectively. CIDI was used to measure affective disturbances and an add-on instrument to measure PEs. RESULTS: Compared to individuals with neither affective disturbances nor PEs, the JTC bias was more likely to occur in individuals with co-occurring affective disturbances and PEs [moderate psychosis (1-2 PEs): adjusted relative risk ratio (RRR) 1.17, 95% CI 0.98-1.41; and high psychosis (3 or more PEs or psychosis-related help-seeking behaviour): adjusted RRR 1.57, 95% CI 1.19-2.08], but not with affective disturbances and PEs alone, whereas decreased WMP was more likely in all groups. There was some evidence of a dose-response relationship, as JTC bias and decreased WMP were more likely in individuals with affective disturbances as the level of PEs increased or help-seeking behaviour was reported. CONCLUSION: The findings suggest that JTC bias and decreased WMP may contribute to a transdiagnostic phenotype of co-occurring affective disturbances and PEs.

8.
Schizophr Bull ; 44(6): 1175-1179, 2018 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-30169883

RESUMO

Identifying modifiable factors through environmental research may improve mental health outcomes. However, several challenges need to be addressed to optimize the chances of success. By analyzing the Netherlands Mental Health Survey and Incidence Study-2 data, we provide a data-driven illustration of how closely connected the exposures and the mental health outcomes are and how model and variable specifications produce "vibration of effects" (variation of results under multiple different model specifications). Interdependence of exposures is the rule rather than the exception. Therefore, exposure-wide systematic approaches are needed to separate genuine strong signals from selective reporting and dissect sources of heterogeneity. Pre-registration of protocols and analytical plans is still uncommon in environmental research. Different studies often present very different models, including different variables, despite examining the same outcome, even if consistent sets of variables and definitions are available. For datasets that are already collected (and often already analyzed), the exploratory nature of the work should be disclosed. Exploratory analysis should be separated from prospective confirmatory research with truly pre-specified analysis plans. In the era of big-data, where very low P values for trivial effects are detected, several safeguards may be considered to improve inferences, eg, lowering P-value thresholds, prioritizing effect sizes over significance, analyzing pre-specified falsification endpoints, and embracing alternative approaches like false discovery rates and Bayesian methods. Any claims for causality should be cautious and preferably avoided, until intervention effects have been validated. We hope the propositions for amendments presented here may help with meeting these pressing challenges.


Assuntos
Pesquisa Biomédica/normas , Protocolos Clínicos/normas , Interpretação Estatística de Dados , Transtornos Mentais/epidemiologia , Psiquiatria/normas , Inquéritos Epidemiológicos , Humanos , Países Baixos/epidemiologia
9.
Schizophr Bull ; 44(4): 710-719, 2018 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-29701807

RESUMO

Background: The observed link between positive psychotic experiences (PE) and psychosis spectrum disorder (PSD) may be stronger depending on concomitant presence of PE with other dimensions of psychopathology. We examined whether the effect of common risk factors for PSD on PE is additive and whether the impact of risk factors on the occurrence of PE depends on the co-occurrence of other symptom dimensions (affective dysregulation, negative symptoms, and cognitive alteration). Method: Data from the Netherlands Mental Health Survey and Incidence Study 2 were used. Risk factors included childhood adversity, cannabis use, urbanicity, foreign born, hearing impairment, and family history of affective disorders. Logistic regression models were applied to test (1) the additive effect of risk factors (4 levels) on PE and (2) the moderating effects of symptom dimensions on the association between risk factors (present/absent) and PE, using additive interaction, expressed as the interaction contrast ratio. Results: Risk factors were additive: the greater the number of risk factors, the greater the odds of PE. Furthermore, concomitant presence of the other symptom dimensions all increased the impact of risk factors on PE. After controlling for age, sex, and education, only affective dysregulation and negative symptoms remained significant moderators; only affective dysregulation remained a significant moderator if all dimensions were adjusted for each other. Conclusions: Risk factors may not be directly associated with PE but additively give rise to a multidimensional subthreshold state anticipating the multidimensional clinical syndrome. Early motivational and cognitive impairments in the context of PE may be reducible to affective dysregulation.


Assuntos
Suscetibilidade a Doenças , Meio Ambiente , Transtornos Psicóticos/epidemiologia , Transtornos Psicóticos/etiologia , Adolescente , Adulto , Idoso , Feminino , Inquéritos Epidemiológicos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Fatores de Risco , Adulto Jovem
10.
Acta Psychol (Amst) ; 183: 116-123, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29275948

RESUMO

In an item-method directed forgetting paradigm, words are presented one at a time, each followed by an instruction to Remember or Forget; a directed forgetting effect is measured as better subsequent memory for Remember words than Forget words. The dominant view is that the directed forgetting effect arises during encoding due to selective rehearsal of Remember over Forget items. In three experiments we attempted to falsify a strong view that directed forgetting effects in recognition are due only to encoding mechanisms when an item method is used. Across 3 experiments we tested for retrieval-based processes by colour-coding the recognition test items. Black colour provided no information; green colour cued a potential Remember item; and, red colour cued a potential Forget item. Recognition cues were mixed within-blocks in Experiment 1 and between-blocks in Experiments 2 and 3; Experiment 3 added explicit feedback on the accuracy of the recognition decision. Although overall recognition improved with cuing when explicit test performance feedback was added in Experiment 3, in no case was the magnitude of the directed forgetting effect influenced by recognition cueing. Our results argue against a role for retrieval-based strategies that limit recognition of Forget items at test and posit a role for encoding intentions only.


Assuntos
Aprendizagem/fisiologia , Memória/fisiologia , Rememoração Mental/fisiologia , /fisiologia , Sinais (Psicologia) , Feminino , Humanos , Masculino , Adulto Jovem
11.
Front Psychiatry ; 9: 676, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30631285

RESUMO

Given the high prevalence of stress-related mental disorders, their impact on person, family, and society and the paucity of treatment options for most of these disorders, there is currently a pressing need for innovative approaches to deal with these issues and enhance well-being. One approach which has received increasing attention over the last decade is to shift our scientific and clinical focus from risk factors for psychopathology to factors promoting resilience and mental well-being. In order to summarize and evaluate the current state of scientific affairs on the biological basis of resilience, we provide an overview of the literature on animal and human studies of resilience. Because resilience can only truly be operationalized through longitudinal data collection and analyses, we focus primarily on longitudinal studies. This review shows that the concept of resilience is currently being operationalized, measured and even defined in widely variable manners, both within animal and human studies. We further provide an overview of existing and new strategies that could help promote resilience and which are proposed to be implemented more often in clinical situations. Finally, we summarize the challenges the field is facing and provide recommendations for future research.

12.
PLoS One ; 12(8): e0183695, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28832672

RESUMO

BACKGROUND: An association between white noise speech illusion and psychotic symptoms has been reported in patients and their relatives. This supports the theory that bottom-up and top-down perceptual processes are involved in the mechanisms underlying perceptual abnormalities. However, findings in nonclinical populations have been conflicting. OBJECTIVES: The aim of this study was to examine the association between white noise speech illusion and subclinical expression of psychotic symptoms in a nonclinical sample. Findings were compared to previous results to investigate potential methodology dependent differences. METHODS: In a general population adolescent and young adult twin sample (n = 704), the association between white noise speech illusion and subclinical psychotic experiences, using the Structured Interview for Schizotypy-Revised (SIS-R) and the Community Assessment of Psychic Experiences (CAPE), was analyzed using multilevel logistic regression analyses. RESULTS: Perception of any white noise speech illusion was not associated with either positive or negative schizotypy in the general population twin sample, using the method by Galdos et al. (2011) (positive: ORadjusted: 0.82, 95% CI: 0.6-1.12, p = 0.217; negative: ORadjusted: 0.75, 95% CI: 0.56-1.02, p = 0.065) and the method by Catalan et al. (2014) (positive: ORadjusted: 1.11, 95% CI: 0.79-1.57, p = 0.557). No association was found between CAPE scores and speech illusion (ORadjusted: 1.25, 95% CI: 0.88-1.79, p = 0.220). For the Catalan et al. (2014) but not the Galdos et al. (2011) method, a negative association was apparent between positive schizotypy and speech illusion with positive or negative affective valence (ORadjusted: 0.44, 95% CI: 0.24-0.81, p = 0.008). CONCLUSION: Contrary to findings in clinical populations, white noise speech illusion may not be associated with psychosis proneness in nonclinical populations.


Assuntos
Ruído , Transtorno da Personalidade Esquizotípica/fisiopatologia , Fala , Adolescente , Adulto , Feminino , Humanos , Masculino , Adulto Jovem
13.
Adv Exp Med Biol ; 978: 211-236, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28523549

RESUMO

Schizophrenia is a highly heritable psychiatric condition that displays a complex phenotype. A multitude of genetic susceptibility loci have now been identified, but these fail to explain the high heritability estimates of schizophrenia. In addition, epidemiologically relevant environmental risk factors for schizophrenia may lead to permanent changes in brain function. In conjunction with genetic liability, these environmental risk factors-likely through epigenetic mechanisms-may give rise to schizophrenia, a clinical syndrome characterized by florid psychotic symptoms and moderate to severe cognitive impairment. These pathophysiological features point to the involvement of epigenetic processes. Recently, a wave of studies examining aberrant DNA modifications in schizophrenia was published. This chapter aims to comprehensively review the current findings, from both candidate gene studies and genome-wide approaches, on DNA methylation changes in schizophrenia.


Assuntos
Metilação de DNA/genética , Epigênese Genética/genética , Esquizofrenia/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Estudos de Casos e Controles , Transtornos Cognitivos/genética , Metilação de DNA/fisiologia , Estudos de Associação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurotransmissores/genética , Neurotransmissores/metabolismo , Transtornos Psicóticos/genética , Esquizofrenia/metabolismo
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