In this cohort profile article we describe the lifetime major depressive disorder (MDD) database that has been established as part of the BIObanks Netherlands Internet Collaboration (BIONIC). Across the Netherlands we collected data on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) lifetime MDD diagnosis in 132,850 Dutch individuals. Currently, N = 66,684 of these also have genomewide single nucleotide polymorphism (SNP) data. We initiated this project because the complex genetic basis of MDD requires large population-wide studies with uniform in-depth phenotyping. For standardized phenotyping we developed the LIDAS (LIfetime Depression Assessment Survey), which then was used to measure MDD in 11 Dutch cohorts. Data from these cohorts were combined with diagnostic interview depression data from 5 clinical cohorts to create a dataset of N = 29,650 lifetime MDD cases (22%) meeting DSM-5 criteria and 94,300 screened controls. In addition, genomewide genotype data from the cohorts were assembled into a genomewide association study (GWAS) dataset of N = 66,684 Dutch individuals (25.3% cases). Phenotype data include DSM-5-based MDD diagnoses, sociodemographic variables, information on lifestyle and BMI, characteristics of depressive symptoms and episodes, and psychiatric diagnosis and treatment history. We describe the establishment and harmonization of the BIONIC phenotype and GWAS datasets and provide an overview of the available information and sample characteristics. Our next step is the GWAS of lifetime MDD in the Netherlands, with future plans including fine-grained genetic analyses of depression characteristics, international collaborations and multi-omics studies.

Bullying research has shown repeatedly that victims of bullying have an increased risk for later internalizing problems and bullies have an increased risk for later externalizing problems. Bullying involvement is often, either explicitly or implicitly, presented as part of a causal mechanism for maladjustment. However, genetic vulnerability may confound the reported associations. This study examined to what extent genetic vulnerability can account for the reported associations between bullying involvement (age 11-14) and later internalizing and externalizing problems (age 16), using data from the TRacking Adolescents' Individual Lives Survey (n = 1604). Because polygenic scores capture only a fraction of the total genetic effect, they were extrapolated to the size of single-nucleotide polymorphism and twin heritability estimates to examine genetic confounding while controlling for (hypothetical) polygenic scores that fully capture the genetic effect. Genetic vulnerability for internalizing and externalizing problems confounded, respectively, the association between bullying victimization and later internalizing problems, and the association between bullying perpetration and later externalizing problems. As such, this study showcases a method that can be broadly used to assess the magnitude of genetic confounding. Caution is, however, warranted in interpreting particularly the less straightforward extrapolations of polygenic scores to the size of twin heritability estimates.

We applied network analysis combined with community detection algorithms to examine how adverse experiences (AEs) (e.g., abuse, bullying victimization, financial difficulties) are, individually and conjunctively, associated with emotional and behavioral problems at age fourteen in the Dutch TRacking Adolescents’ Individual Lives Survey (TRAILS, N = 1880, 52.2% female). We found that bullying victimization, peer rejection, parental mental health problems, emotional abuse, and sexual abuse were the only AEs directly contributing to risk of emotional problems. Parental divorce and emotional abuse were the only AEs directly contributing to risk of behavioral problems. Most AEs (e.g., parental employment, parental physical illness) were not conditionally associated with emotional and behavioral problems but may nevertheless contribute to emotional and behavioral problems via associations with other AEs (e.g., parental unemployment and emotional abuse). Community detection algorithms suggested that many of the AEs cluster together (e.g., physical abuse, emotional abuse, and sexual abuse; financial difficulties and parental unemployment), sometimes with emotional and behavioral problems (e.g., bullying victimization, peer rejection and emotional problems). Our findings shed light on how individual AEs contribute to risks of emotional and behavioral problems directly, and indirectly through associations with other AEs.

Social withdrawal and social anxiety are believed to have a bidirectional influence on one another, but it is unknown if their relationship is bidirectional, especially within person, and if peer experiences influence this relationship. We investigated temporal sequencing and the strength of effects between social withdrawal and social anxiety, and the roles of peer victimization and acceptance in the pathways. Participants were 2,772 adolescents from the population-based and clinically referred cohorts of the Tracking Adolescents' Individual Lives Survey. Self- and parent-reported withdrawal, and self-reported social anxiety, peer victimization, and perceived peer acceptance were assessed at 11, 13, and 16 years. Random-intercept cross-lagged panel models were used to investigate within-person associations between these variables. There was no feedback loop between withdrawal and social anxiety. Social withdrawal did not predict social anxiety at any age. Social anxiety at 11 years predicted increased self-reported withdrawal at 13 years. Negative peer experiences predicted increased self- and parent-reported withdrawal at 13 years and increased parent-reported withdrawal at 16 years. In turn, self-reported withdrawal at 13 years predicted negative peer experiences at 16 years. In conclusion, adolescents became more withdrawn when they became more socially anxious or experienced greater peer problems, and increasing withdrawal predicted greater victimization and lower acceptance.

The adaptive calibration model (ACM) is a theory of developmental programing focusing on calibration of stress response systems and associated life history strategies to local environmental conditions. In this article, we tested some key predictions of the ACM in a longitudinal study of Dutch adolescent males (11–16 years old; N = 351). Measures of sympathetic, parasympathetic, and adrenocortical activation, reactivity to, and recovery from social–evaluative stress validated the four-pattern taxonomy of the ACM via latent profile analysis, though with some deviations from expected patterns. The physiological profiles generally showed predicted associations with antecedent measures of familial and ecological conditions and life stress; as expected, high- and low-responsivity patterns were found under both low-stress and high-stress family conditions. The four patterns were also differentially associated with aggressive/rule-breaking behavior and withdrawn/depressed behavior. This study provides measured support for key predictions of the ACM and highlights important empirical issues and methodological challenges for future research.

Approximately half of the variation in wellbeing measures overlaps with variation in personality traits. Studies of non-human primate pedigrees and human twins suggest that this is due to common genetic influences. We tested whether personality polygenic scores for the NEO Five-Factor Inventory (NEO-FFI) domains and for item response theory (IRT) derived extraversion and neuroticism scores predict variance in wellbeing measures. Polygenic scores were based on published genome-wide association (GWA) results in over 17,000 individuals for the NEO-FFI and in over 63,000 for the IRT extraversion and neuroticism traits. The NEO-FFI polygenic scores were used to predict life satisfaction in 7 cohorts, positive affect in 12 cohorts, and general wellbeing in 1 cohort (maximal N = 46,508). Meta-analysis of these results showed no significant association between NEO-FFI personality polygenic scores and the wellbeing measures. IRT extraversion and neuroticism polygenic scores were used to predict life satisfaction and positive affect in almost 37,000 individuals from UK Biobank. Significant positive associations (effect sizes <0.05%) were observed between the extraversion polygenic score and wellbeing measures, and a negative association was observed between the polygenic neuroticism score and life satisfaction. Furthermore, using GWA data, genetic correlations of -0.49 and -0.55 were estimated between neuroticism with life satisfaction and positive affect, respectively. The moderate genetic correlation between neuroticism and wellbeing is in line with twin research showing that genetic influences on wellbeing are also shared with other independent personality domains.

In contrast to victimization, prior research on the antecedents and outcomes of bullying perpetration has provided little conclusive knowledge. Some adolescent bullies may be well adjusted and popular among peers, while other bullies are rejected and lack self-control. There is also great variation in the outcomes, with a number of studies (but not all) showing increased risk for externalizing and internalizing problems. We used a developmental framework and data from 2,230 participants of the Dutch Tracking Adolescents’ Individual Lives Survey (TRAILS) to examine bullying perpetration across adolescence, to test the links with various antecedents in preadolescence, and to elucidate the outcomes in early adulthood. Latent growth models indicated significant variance in initial bullying perpetration levels and an overall decrease between pre- and late adolescence. Individual, family, and peer factors were associated with initial levels and partially associated with bullying development over time. Bullying perpetration was linked to later maladjustment and substance use, although only in girls. Finally, bullying perpetration appears to function as an intermediate variable between preadolescent individual, family, and peer risk and substance use more than 10 years later. These results have important implications for understanding the gender-specific nature of bullying perpetration and its outcomes and for demonstrating that bullying carries early risk into adulthood.

Childhood adversities have been proposed to modify later stress sensitivity and risk of depressive disorder in several ways: by stress sensitization, stress amplification, and stress inoculation. Combining these models, we hypothesized that childhood adversities would increase risk of early, but not later, onsets of depression (Hypothesis 1). In those without an early onset, childhood adversities were hypothesized to predict a relatively low risk of depression in high-stress conditions (Hypothesis 2a) and a relatively high risk of depression in low-stress conditions (Hypothesis 2b), compared to no childhood adversities. These hypotheses were tested in 1,584 participants of the Tracking Adolescents' Individual Lives Survey, a prospective cohort study of adolescents. Childhood adversities were assessed retrospectively at ages 11 and 13.5, using self-reports and parent reports. Lifetime DSM-IV major depressive episodes were assessed at age 19, by means of the Composite International Diagnostic Interview. Stressful life events during adolescence were established using interview-based contextual ratings of personal and network events. The results provided support for all hypotheses, regardless of the informant and timeframe used to assess childhood adversities and regardless of the nature (personal vs. network, dependent vs. independent) of recent stressful events. These findings suggest that age at first onset of depression may be an effective marker to distinguish between various types of reaction patterns.

The biological sensitivity to context hypothesis posits that high physiological reactivity (i.e., increases in arousal from baseline) constitutes heightened sensitivity to environmental influences, for better or worse. To test this hypothesis, we examined the interactive effects of family cohesion and heart rate reactivity to a public speaking task on aggressive/rule-breaking and prosocial behavior in a large sample of adolescents (N = 679; M age = 16.14). Multivariate analyses revealed small- to medium-sized main effects of lower family cohesion and lower heart rate reactivity on higher levels of aggressive/rule-breaking and lower levels of prosocial behavior. Although there was some evidence of three-way interactions among family cohesion, heart rate reactivity, and sex in predicting these outcome variables, these interactions were not in the direction predicted by the biological sensitivity to context hypothesis. Instead, heightened reactivity appeared to operate as a protective factor against family adversity, rather than as a susceptibility factor. The results of the present study raise the possibility that stress reactivity may no longer operate as a mechanism of differential susceptibility in adolescence.

The effects of divorce on children's behavioral development have proven to be quite varied across studies, and most developmental and family scholars today appreciate the great heterogeneity in divorce effects. Thus, this inquiry sought to determine whether select dopaminergic genes previously associated with externalizing behavior and/or found to moderate diverse environmental effects (dopamine receptors D2 and D4, catechol-O-methyltransferase) might moderate divorce effects on adolescent self-reported externalizing problems; and, if so, whether evidence of gene–environment (G × E) interaction would prove consistent with diathesis–stress or differential-susceptibility models of environmental action. Data from the first and third wave of the Dutch Tracking Adolescents' Individual Lives Survey (n = 1,134) revealed some evidence of G × E interaction reflecting diathesis–stress but not differential susceptibility. It is intriguing that some evidence pointed to “vantage sensitivity,” which are benefits accruing to those with a specific genotype when their parents remained together, the exact opposite of diathesis–stress. The limits of this work are considered, especially with regard to the conditions for testing differential susceptibility, and future directions are outlined.

Effortful control is thought to foster adaptive action in defensive contexts and may thereby protect individuals against anxious inhibition and focus on their own distress. We examined if effortful control predicted adolescents' perceived arousal, unpleasantness, and control as well as autonomic (heart rate [HR]) and hypothalamic–pituitary–adrenal axis (cortisol) responses during social stress. The data came from a focus sample of the Tracking Adolescents' Individual Lives Survey, a prospective population study of Dutch adolescents (N = 715, 50.9% girls; mean age = 16.11, SD = 0.59), who participated in a laboratory session including a social stress task (public speaking and mental arithmetic). Perceived and physiological stress measures were assessed before, during, and after the social stress task. Effortful control was measured using various questionnaires and informants, as well as by means of a reaction time (RT) task assessing response inhibition. Overall, adolescents with high questionnaire-based effortful control tended to feel more relaxed, pleasant, and in control during the laboratory session than adolescents with lower levels of control and had stronger HR responses to the stress test. Adolescent girls with high inhibitory control as measured by the RT task also had strong HR responses, but inhibitory control was associated with high rather than low perceived arousal. Our results suggest that both questionnaire and RT measures of effortful control predict strong HR responses to challenging situations, but associational patterns diverge with regard to perceived stress measures.

This study examined the extent to which effortful control moderated the risk of internalizing or externalizing problems associated with high negative emotionality in a Dutch population sample of pre- and early adolescents (N = 1,922). Internalizing and externalizing problems were assessed with the Child Behavior Checklist, Youth Self-Report, and Teacher Checklist of Psychopathology. Temperament (effortful control, fearfulness, frustration) was assessed with the parent version of the Revised Early Adolescent Temperament Questionnaire. The effects of fearfulness and frustration appeared to be attenuated by high levels of effortful control. The associations differed between the two domains of mental health investigated: effortful control reduced the effect of fearfulness on internalizing problems and the effect of frustration on externalizing problems. The effects were stronger for externalizing problems and similar for preadolescent (age 11) and adolescent (age 13/14) outcomes.This research is part of the Tracking Adolescents' Individual Lives Survey (TRAILS). Participating centers of TRAILS include various Departments of the University of Groningen, Erasmus Medical Center of Rotterdam, University of Nijmegen, Trimbos Institute, and University of Utrecht, The Netherlands. TRAILS is financially supported by grants from The Netherlands Organization for Scientific Research (GB-MW 940-38-011, GB-MAG 480-01-006, ZonMw 100.001.001, and NWO 175.010.2003.005) and the Department of Justice (WODC), and by the participating centers.

Background. Neuroticism is widely used as an explanatory concept in etiological research of psychopathology. In order to clarify what neuroticism actually represents, we investigated the genetic association between neuroticism and cardiovascular measures.

Method. In 125 female twin pairs (18–30 years), electrocardiogram and continuous finger blood pressure were assessed during two rest and two mental stress conditions. Mean values for baroreflex sensitivity (BRS), heart rate variability (HRV) and inter-beat interval (IBI) were calculated for each condition. Neuroticism was assessed by multiple questionnaires. Multivariate genetic model-fitting analyses were used to investigate the genetic correlation between latent neuroticism and the cardiovascular autonomic nervous system (ANS) measures.

Results. Neuroticism was negatively correlated to BRS and HRV. Neuroticism was not correlated to IBI. For BRS, this phenotypical relation was entirely determined by shared genetic influences. For HRV, the genetic contribution to the phenotypical correlation was not significant, but the proportions of explained covariance showed a trend of more genetic than environmental influences on the phenotypical relationship.

Conclusions. High neuroticism is associated with a deregulated ANS. Pleiotropic genetic effects may be partly responsible for this effect.

This study investigates how temperament factors are linked to internalizing and externalizing problems in a Dutch population sample of preadolescents (N = 2230). Internalizing and externalizing problems were assessed by the Child Behavior Checklist and the Youth Self-Report and temperament was evaluated by the parent-version of the Revised Early Adolescent Temperament Questionnaire. Temperament profiles were examined in children with (a) neither internalizing nor externalizing problems, (b) only internalizing problems, (c) only externalizing problems, and (d) both internalizing and externalizing problems. The results suggest clearly diverging temperament profiles for these groups of children, with High-Intensity Pleasure and Shyness (representing the broad dimension of Surgency) steering the conditional probability of internalizing and externalizing problems (direction markers), Frustration mainly being related to maladaptation in general (severity marker), and Fear and Effortful Control being associated with both the severity and the direction of internalizing and externalizing problems, respectively. Girls and boys differed in the distribution across the problem groups, but the associations between temperament and psychopathology were comparable for both genders.This research is part of the Tracking Adolescents' Individual Lives Survey (TRAILS). Participating centers of TRAILS include various Departments of the University of Groningen, the Erasmus Medical Center of Rotterdam, the Vrije University of Amsterdam, the University of Nijmegen, and the Trimbos Institute, The Netherlands. TRAILS is financially supported by grants from the Netherlands Organization for Scientific Research (GB-MW 940-38-011, GB-MAG 480-01-006, ZonMw 100-001-001) and the Ministry of Justice (to F.C.V.) and by the participating centers.

The extent of social dysfunctioning and its relationship to psychological disorders among Dutch primary care patients was examined. Social dysfunctioning in these patients was rather limited, but was more pronounced in patients with a psychological disorder than in those without. Disabilities were largely restricted to the occupational and social roles, with family role functioning and self-care relatively intact. Social dysfunctioning was moderately related to psychopathology, with higher levels of dysfunctioning in more severe and depressed cases. The extent of social dysfunctioning among patients with both anxiety and depression was similar to that of patients with a single diagnosis of depression. Depressed patients had a similar level of dysfunctioning to non-psychotic psychiatric out-patients. Analyses regarding the effects of diagnosis and severity on social dysfunctioning revealed considerable overlap between these two aspects of psychopathology. This study supports the need for a simultaneous but separate assessment of psychopathology and social dysfunctioning. However, future research should incorporate additional predictors of social dysfunctioning (e.g. personality, life events, long-term difficulties, physical disorders), and prospective studies should be conducted to clarify the temporal sequences of symptom severity, diagnosis, and comorbidity on the one hand, and social dysfunctioning on the other.