Polygenic liability for schizophrenia and childhood adversity influences daily-life emotion dysregulation and psychosis proneness.

OBJECTIVE: To test whether polygenic risk score for schizophrenia (PRS-S) interacts with childhood adversity and daily-life stressors to influence momentary mental state domains (negative affect, positive affect, and subtle psychosis expression) and stress-sensitivity measures. METHODS: The data were retrieved from a general population twin cohort including 593 adolescents and young adults. Childhood adversity was assessed using the Childhood Trauma Questionnaire. Daily-life stressors and momentary mental state domains were measured using ecological momentary assessment. PRS-S was trained on the latest Psychiatric Genetics Consortium schizophrenia meta-analysis. The analyses were conducted using multilevel mixed-effects tobit regression models. RESULTS: Both childhood adversity and daily-life stressors were associated with increased negative affect, decreased positive affect, and increased subtle psychosis expression, while PRS-S was only associated with increased positive affect. No gene-environment correlation was detected. There is novel evidence for interaction effects between PRS-S and childhood adversity to influence momentary mental states [negative affect (b = 0.07, P = 0.013), positive affect (b = -0.05, P = 0.043), and subtle psychosis expression (b = 0.11, P = 0.007)] and stress-sensitivity measures. CONCLUSION: Exposure to childhood adversities, particularly in individuals with high PRS-S, is pleiotropically associated with emotion dysregulation and psychosis proneness.

Is sensitivity to daily stress predictive of onset or persistence of psychopathology?

PURPOSE: The aim of the current study was to replicate findings in adults indicating that higher sensitivity to stressful events is predictive of both onset and persistence of psychopathological symptoms in a sample of adolescents and young adults. In addition, we tested the hypothesis that sensitivity to mild stressors in particular is predictive of the developmental course of psychopathology. METHODS: We analyzed experience sampling and questionnaire data collected at baseline and one-year follow-up of 445 adolescent and young adult twins and non-twin siblings (age range: 15-34). Linear multilevel regression was used for the replication analyses. To test if affective sensitivity to mild stressors in particular was associated with follow-up symptoms, we used a categorical approach adding variables on affective sensitivity to mild, moderate and severe daily stressors to the model. RESULTS: Linear analyses showed that emotional stress reactivity was not associated with onset (ß=.02; P=.56) or persistence (ß=-.01; P=.78) of symptoms. There was a significant effect of baseline symptom score (ß=.53; P<.001) and average negative affect (NA: ß=.19; P<.001) on follow-up symptoms. Using the categorical approach, we found that affective sensitivity to mild (ß=.25; P<.001), but not moderate (ß=-.03; P=.65) or severe (ß=-.06; P=.42), stressors was associated with symptom persistence one year later. DISCUSSION: We were unable to replicate previous findings relating stress sensitivity linearly to symptom onset or persistence in a younger sample. Whereas sensitivity to more severe stressors may reflect adaptive coping, high sensitivity to the mildest of daily stressors may indicate an increased risk for psychopathology.

Gold-silver catalyzed straightforward one pot synthesis of pyrano[3,4-b]pyrrol-7(1H)-ones.

Pyrano[3,4-b]pyrrol-7(1H)-one is a bicyclic structure that is rarely described in the literature but is found in numerous polycyclic natural products as lamellarins. This work presents a one-pot synthesis of pyrano[3,4-b]pyrrol-7(1H)-one substituted in the 2- and 5-position. The reaction proceeds via a one-pot two step 5-endo-dig and 6-endo-dig cyclization catalyzed by a cationic gold complex with high regioselectivity.

Positive emotions from social company in women with persisting subclinical psychosis: lessons from daily life.

OBJECTIVE: Altered social reward functioning is associated with psychosis irrespective of stage and severity. Examining the role of social reward functioning prospectively in relation to psychotic experiences before these become persistent and potentially disabling can aid in elucidating social mechanisms that induce shifts toward more severe psychotic states, without the confounding effects of clinical disorder. METHOD: In a longitudinal general population sample (N = 566), the experience sampling method (repetitive random sampling of momentary emotions and social context) was used to assess daily life social functioning at baseline. Persistence of subclinical psychotic experiences was based on the Community Assessment of Psychic Experiences assessed three times over 14 months. Analyses examined to what degree i) social context and ii) appreciation thereof differentiated between those who did and did not develop persistent psychotic experiences. RESULTS: Although individuals with persistent psychotic experiences did not differ in overall level of positive effect, the amount of time spent alone or the level of social satisfaction compared to individuals without persistent psychotic experiences, they were more sensitive to the rewarding effects of social company. CONCLUSION: Alterations in social reward experience may form one of the mechanisms that precede the development of the extended psychosis phenotype over time.

Intrauterine environment and cognitive development in young twins.

Intrauterine factors important for cognitive development, such as birth weight, chorionicity and umbilical cord characteristics were investigated. A total of 663 twin pairs completed the Wechsler Intelligence Scale for Children-Revised and scores were available for Performance, Verbal and Total Intelligence Quotient (IQ). The intrauterine factors examined were birth weight, placental weight and morphology, cord knots, cord length and cord insertion. IQ scores for the varying levels of the intrauterine markers adjusting for gender and gestational age were calculated. The heritability of IQ and the association between IQ and intrauterine environment were examined. Twins with lower birth weight and cord knots had lower IQ scores. The aetiology of IQ is largely distinct from that of birth weight and cord knots, and non-shared environment may influence the observed relationships.

Deconstructing the familiality of variability in momentary negative and positive affect.

OBJECTIVE: The daily life, affective phenotypes of momentary negative affect (NA), positive affect (PA) variability and NA variability are associated with future depressive symptomatology. This study investigates the extent to which genetic and environmental factors contribute to the inter-individual differences in these daily life, affective phenotypes. METHOD: Two hundred and seventy-nine female twins from the Flemish (Belgium) general population participated in an experience sampling study measuring affect in daily life. Structural equation modelling was used to fit univariate and bivariate models. RESULTS: Genetic factors explained, respectively, 18%, 18% and 35% of the inter-individual differences in momentary NA, PA variability and NA variability. Non-shared environmental factors were found to explain the remaining inter-individual variation. In addition, 41% of the association between positive and NA variability was attributed to shared genetic factors. CONCLUSION: Results of this study show that daily life patterns of affective expression are subject to substantial environmental influence. Prospective assessments of the effect of interventions on these expressions may therefore represent a powerful tool to prevent transition from subclinical depressive symptomatology to a clinical outcome or to reduce symptomatology in those with clinical depression.

Disentangling the causal inter-relationship between negative life events and depressive symptoms in women: a longitudinal twin study.

BACKGROUND: Negative life events are strongly associated with the development of depression. However, the etiologic relationship between life events and depression is complex. Evidence suggests that life events can cause depression, and depression increases the risk for life events. Additionally, third factors influencing both phenotypes may be involved. In this work we sought to disentangle these relationships using a genetically informative longitudinal design. METHOD: Adult female twins (n=536, including 281 twin pairs) were followed up for measurements of negative life event exposure and depressive symptoms. Four follow-ups were completed, each approximately 3 months apart. Model fitting was carried out using the Mx program. RESULTS: The best-fitting model included causal paths from life events to depressive symptoms for genetic and shared environmental risk factors, whereas paths from depressive symptoms to life events were apparent for shared environmental factors. Shared latent influence on both phenotypes was found for individual-specific effects. CONCLUSIONS: Life events and depressive symptoms have complex inter-relationships that differ across sources of variance. The results of the model, if replicated, indicate that reducing life event exposure would reduce depressive symptoms and that lowering depressive symptoms would decrease the occurrence of negative life events.

Evidence that genes for depression impact on the pathway from trauma to psychotic-like symptoms by occasioning emotional dysregulation.

BACKGROUND: Genes for depression may act by making individuals more sensitive to childhood trauma. Given that childhood adversity is a risk factor for adult psychosis and symptoms of depression and psychosis tend to cluster within individuals and families, the aim was to examine whether the association between childhood adversity and psychotic-like symptoms is moderated by genetic liability for depression. A secondary aim was to determine to what degree a depression-related increase in stress sensitivity or depressive symptoms themselves occasioned the moderating effect. METHOD: Female twins (n=508) completed both prospective and retrospective questionnaires regarding childhood adversity [the Symptom Checklist-90 - Revised (SCL-90-R) and SCID-I (psychotic symptoms)] and psychotic trait liability [the Community Assessment of Psychic Experiences (CAPE)]. Stress sensitivity was indexed by appraisals of event-related stress and negative affect (NA) in the flow of daily life, assessed with momentary assessment technology for five consecutive days. Multilevel regression analyses were used to examine moderation of childhood adversity by genetic liability for depression in the prediction of follow-up psychotic experiences. RESULTS: The effect of childhood adversity was significantly moderated by genetic vulnerability for depression in the model of both follow-up psychotic experiences (SCL-90-R) and follow-up psychotic trait liability (CAPE). The moderation by genetic liability was mediated by depressive experience but not by stress sensitivity. CONCLUSIONS: Genetic liability for depression may potentiate the pathway from childhood adversity to psychotic-like symptoms through dysfunctional emotional processing of anomalous experiences associated with childhood trauma.

Neuroticism explained? From a non-informative vulnerability marker to informative person-context interactions in the realm of daily life.

OBJECTIVES: Despite the well-replicated finding that neuroticism is associated with increased susceptibility for psychopathology, it remains unclear what 'vulnerability as indexed by neuroticism' represents in terms of everyday life emotional processes. This study examined the association between neuroticism and six phenotypes of daily life emotional responses: positive affect (PA), negative affect (NA), PA variability, NA variability, stress sensitivity, and reward experience, and investigated the contribution of genetic and environmental factors to these associations. DESIGN: A prospective cohort study in a population-based sample of 416 adult female twins. METHOD: A momentary assessment approach (experience sampling method) was used to collect multiple assessments of affect in daily life. Neuroticism was assessed with the Eysenck Personality Scale. Multi-level regression analyses were carried out to examine the association between neuroticism and the phenotypes of daily life emotional responses. Cross-twin, cross-trait analyses, and bivariate structural equation modelling (SEM) were performed in order to investigate the nature of these associations. RESULTS: A high neuroticism score was associated with lower momentary PA levels and increased NA variability, independent of momentary NA, PA variability, stress sensitivity, and reward experience. Both the cross-twin, cross-trait analyses, and the bivariate SEM showed that unique, non-shared environmental factors drive the association between neuroticism and PA and that the association between neuroticism and increased NA variability is based on shared genetic factors as well as individual-specific environmental factors. CONCLUSIONS: Neuroticism as measured by Eysenck questionnaire may index an environmental risk for decreased daily life PA levels and a genetic as well as an environmental risk for increased NA variability. Decomposing the broad measure of neuroticism into measurable persons-context interactions increases its 'informative' value in explaining psychopathology.

No major role for X-inactivation in variations of intelligence and behavioral problems at middle childhood.

Although members of monozygotic (MZ) twin pairs are identical in genomic sequence, epigenetic mechanisms may occasion difference in gene expression and, consequently, twin discordance in complex traits. Recent work suggests that the epigenetic process of X-inactivation in female individuals may impact on intelligence and child behavioral problems. The timing of X-inactivation has been linked to chorionic splitting in MZ twins. Dichorionic monozygotic (DC-MZ) twinning, unlike monochorionic monozygotic (MC-MZ) twinning, occurs prior to the time of X-inactivation in female organisms. Therefore, the hypothesis of a causal role of X-inactivation in intelligence and behavioral problems can be analyzed by modeling the statistical interaction between sex and chorion type for within-pair differences in these traits in MZ twins. In this study, the effect of X-inactivation on childhood behavioral problems, measured with the CBCL, was studied in a sample of 324 MZ twin pairs from the EFPTS and the effect of X-inactivation on IQ was studied in a sample of 272 twin pairs from the same twin survey. Information on chorion type, gestational age, and birth weight was additionally collated. No significant statistical interaction was found between sex and chorion type, indicating that X-inactivation is not likely involved in variations in intelligence or behavioral problems in middle childhood. Further studies are required to replicate these findings and may explore the role of X-inactivation at different ages or at the extreme scores in the spectrum of intelligence and behavioral problems or may focus on other epigenetic mechanisms.

Meeting risk with resilience: high daily life reward experience preserves mental health.

OBJECTIVE: To examine prospectively whether high reward experience (the ability to generate positive affect boosts from pleasurable daily events) protects against affective symptoms and whether environmental or genetic risk factors moderate protective effects. METHOD: At baseline, 498 female twins participated in an experience sampling study measuring reward experience in daily life. They also completed questionnaires on childhood adversity and recent stressful life events (SLE). Affective symptoms were measured at baseline and at four follow-ups using SCL-90 anxiety and depression subscales. Co-twin affective symptoms were used as indicators of genetic risk. RESULTS: Baseline reward experience did not predict follow-up affective symptoms, regardless of level of genetic risk. However, high reward experience was associated with reduced future affective symptoms after previous exposure to childhood adversity or recent SLE. CONCLUSION: High daily life reward experience increases resilience after environmental adversity; modification of reward experience may constitute a novel area of therapeutic intervention.

Unveiling patterns of affective responses in daily life may improve outcome prediction in depression: a momentary assessment study.

OBJECTIVE: Daily life affective responses are closely linked to vulnerability and resilience in depression. Prediction of future clinical course may be improved if information on daily life emotional response patterns is taken into account. METHOD: Female subjects with a history of major depression (n=83), recruited from a population twin register, participated in a longitudinal study using momentary assessment technology with 4 follow-up measurements. The effect of baseline daily life emotional response patterns (affect variability, stress-sensitivity and reward experience) on follow-up depressive symptomatology was examined. RESULTS: Both reward experience (B=-0.30, p=0.001) and negative affect variability (B=0.46, p=0.001) predicted future negative affective symptoms independent of all other dynamic emotional patterns and conventional predictors. CONCLUSION: Daily life information on dynamic emotional patterns adds to the prediction of future clinical course, independent of severity of symptoms and neuroticism score. Better prediction of course may improve decision-making regarding quantitative and qualitative aspects of treatment.

Cognition as predictor of current and follow-up depressive symptoms in the general population.

OBJECTIVE: Previous studies have reported an association between depression and poor cognitive functioning. Unknown is to what degree such associations are merely state-related or reflect an enduring depression vulnerability. This study examined whether cognitive deficits predict current and/or follow-up (sub)clinical depressive symptoms in the general population. METHOD: A population-based sample of 569 female twins and 43 of their sisters completed a neuropsychological battery. Cross-sectional and prospective associations between depressive symptoms measured at the subclinical [Symptom Checklist-90 (SCL-90)] and clinical level (Structured Clinical Interview for DSM-IV disorders) and neuropsychological factors (episodic memory and information processing speed) were examined. RESULTS: Structured Clinical Interview for DSM-IV disorders baseline depressive symptoms were significantly associated with information processing speed but not with episodic memory. Episodic memory was significantly associated with follow-up SCL-90 depressive symptoms. CONCLUSION: Being depressed is accompanied by slower information processing. Poor memory functioning may be a predictor for the onset of subclinical depressive symptoms.

Subtle gene-environment interactions driving paranoia in daily life.

It has been suggested that genes impact on the degree to which minor daily stressors cause variation in the intensity of subtle paranoid experiences. The objective of the present study was to test the hypothesis that catechol-O-methyltransferase (COMT) Val(158)Met and brain-derived neurotrophic factor (BDNF) Val(66)Met in part mediate genetic effects on paranoid reactivity to minor stressors. In a general population sample of 579 young adult female twins, on the one hand, appraisals of (1) event-related stress and (2) social stress and, on the other hand, feelings of paranoia in the flow of daily life were assessed using momentary assessment technology for five consecutive days. Multilevel regression analyses were used to examine moderation of daily life stress-induced paranoia by COMT Val(158)Met and BDNF Val(66)Met genotypes. Catechol-O-methyltransferase Val carriers displayed more feelings of paranoia in response to event stress compared with Met carriers. Brain-derived neurotrophic factor Met carriers showed more social-stress-induced paranoia than individuals with the Val/Val genotype. Thus, paranoia in the flow of daily life may be the result of gene-environment interactions that can be traced to different types of stress being moderated by different types of genetic variation.

Does reactivity to stress cosegregate with subclinical psychosis? A general population twin study.

OBJECTIVE: This study assessed the relationship between stress reactivity (trait 1) and psychosis (trait 2) across genetically related persons (cross-twin, cross-trait design) to examine whether stress reactivity is an uncontaminated and unconfounded familial marker of psychosis risk. METHOD: Reactivity to stress and subclinical psychotic experiences were assessed in 289 female, general population twin-pairs. Cross-trait, within-twin associations investigating the association between stress reactivity and subclinical psychotic experiences in each person, were calculated. In addition, cross-trait, cross-twin associations were calculated to assess whether stress reactivity in one twin was moderated by subclinical psychotic experiences in the co-twin. RESULTS: Cross-trait, within-twin analyses showed significant associations between stress reactivity and subclinical psychotic experiences in each person. In addition, the cross-trait cross-twin analyses showed that stress reactivity in twin 1 was significantly moderated by subclinical experiences in the co-twin. CONCLUSION: The results suggest that the psychosis phenotype cosegregates with increased emotional reactivity to stress in daily life.

Mechanisms of gene-environment interactions in depression: evidence that genes potentiate multiple sources of adversity.

BACKGROUND: Previous work suggests that daily life stress-sensitivity may be an intermediary phenotype associated with both genetic risk for depression and developmental stress exposures. In the current analysis we hypothesized that genetic risk for depression and three environmental exposures over the course of development [prenatal stress, childhood adversity and adult negative life events (NLEs)] combine synergistically to produce the phenotype of stress-sensitivity. METHOD: Twin pairs (n=279) participated in a momentary assessment study using the Experience Sampling Method (ESM), collecting appraisals of stress and negative affect (NA) in the flow of daily life. Prospective data on birthweight and gestational age, questionnaire data on childhood adversity and recent NLEs, and interview data on depression were used in the analyses. Daily life stress-sensitivity was modelled as the effect of ESM daily life stress appraisals on ESM NA. RESULTS: All three developmental stress exposures were moderated by genetic vulnerability, modelled as dizygotic (DZ) or monozygotic (MZ) co-twin depression status, in their effect on daily life stress-sensitivity. Effects were much stronger in participants with MZ co-twin depression and a little stronger in participants with DZ co-twin depression status, compared to those without co-twin depression. NLE main effects and NLE genetic moderation were reducible to birthweight and childhood adversity. CONCLUSIONS: The findings are consistent with the hypothesis that adult daily life stress-sensitivity is the result of sensitization processes initiated by developmental stress exposures. Genes associated with depression may act by accelerating the process of stress-induced sensitization.

Heritability of borderline personality disorder features is similar across three countries.

BACKGROUND: Most of our knowledge about borderline personality disorder features has been obtained through the study of clinical samples. Although these studies are important in their own right, they are limited in their ability to address certain important epidemiological and aetiological questions such as the degree to which there is a genetic influence on the manifestation of borderline personality disorder features. Though family history studies of borderline personality disorder indicate genetic influences, there have been very few twin studies and the degree of genetic influence on borderline personality disorder remains unclear. METHOD: Data were drawn from twin samples from The Netherlands (n=3918), Belgium (n=904) and Australia (n=674). In total, data were available on 5496 twins between the ages of 18 and 86 years from 3644 families who participated in the study by completion of a mailed self-report questionnaire on borderline personality disorder features. RESULTS: In all countries, females scored higher than males and there was a general tendency for younger adults to endorse more borderline personality disorder features than older adults. Model-fitting results showed that additive genetic influences explain 42% of the variation in borderline personality disorder features in both men and women and that this heritability estimate is similar across The Netherlands, Belgium and Australia. Unique environmental influences explain the remaining 58% of the variance. CONCLUSION: Genetic factors play a role in individual differences in borderline personality disorder features in Western society.

Neurocognitive consequences of surgically corrected congenital heart defects: A review.

With advances in surgical procedures, neuropsychological assessment after congenital heart defects and pre, peri- and/or postoperative predictors of adverse outcome has become an important focus in research. We aim to summarize neuropsychological sequelae associated with different types of congenital heart defects, critically review the methodology used in more than 20 empirical studies that were retrieved from biomedical electronic search engines, and identify possible directions for future research. Despite the lack of adequate control groups and long-term studies, there seem to be some cognitive deficits. The largest group of children with isolated congenital heart defects present with normal intellectual capacities. However, they tend to show language deficits and motor dysfunction. Although performances on memory tasks are good, unambiguous conclusions concerning their attentional and executive functioning are still lacking. Serious behavioral problems are not an issue. In addition to a detailed description of the (neuro) psychological consequences of pediatric cardiac surgery, an overview of the predictors of the cognitive defects is provided.

Chromosome 21 KIR channels in brain development.

Two KIR (K+ Inwardly Rectifying) channel genes have been identified on chromosome 21, in a region associated with important phenotypic features of trisomy 21, including mental retardation: KIR3.2 (GIRK2) and KIR4.2. We analysed the expression of these channel genes in developing human and mouse brains to determine the possible role of the corresponding channels in brain development and function. KIR3.2, which has been extensively studied in the mouse, was found to be expressed in the human cerebellum during development. The KIR4.2 channel is expressed later in development in both mice and humans. We compared the expression of these channels in terms of RNA and protein levels and discussed the potential synergy and consequences of the overexpression of these channels in Down's syndrome brain development.

Child psychopathology and lower cognitive ability: a general population twin study of the causes of association.

Previous work has demonstrated associations between lower cognitive ability and childhood and adult non-psychotic psychopathology. As both cognitive ability (CA) and child psychopathology (CP) are influenced by genetic factors, one explanation for the association is that they are the pleiotropic manifestations of the same underlying genetic factors. The present paper examines three possible causes of the association: additive genetic factors, common environmental factors and individual-specific environmental factors. Three hundred and seventy-six twin pairs from the East Flanders Prospective Twin Survey were examined with the Child Behaviour Checklist and the Wechsler Intelligence Scale for Children-Revised. The cross-twin within-variable, within-twin cross-variable and cross-twin cross-variable correlations were calculated. Using structural equation modelling, bivariate models were fitted. The best fitting model was chosen, based on likelihood and parsimony. The observed phenotypic correlation between CP and CA was -0.19 (95% CI: -0.09, -0.27), with genetic factors accounting for about 84% of the observed correlation. Bivariate model fitting quantified the genetic correlation between CP and CA at -0.27 (95% CI: -0.12, -0.42) and the individual-specific environmental correlation at -0.17 (95% CI: -0.03, -0.31). In children, three different genetic factors may exist: one that solely affects the liability to CP, one that has only an effect on CA and one that influences both CP and CA. While individual-specific environmental factors can influence the liability to both traits, our results suggest that most of the environmental factors that increase the risk of CP do not influence CA and vice versa.