Are Genetic and Environmental Risk Factors for Psychopathology Amplified in Children with Below-Average Intelligence? A Population-Based Twin Study.

There is a negative association between intelligence and psychopathology. We analyzed data on intelligence and psychopathology to assess this association in seven-year-old Dutch twin pairs (ranging from 616 to 14,150 depending on the phenotype) and estimated the degree to which genetic and environmental factors common to intelligence and psychopathology explain the association. Secondly, we examined whether genetic and environmental effects on psychopathology are moderated by intelligence. We found that intelligence, as assessed by psychometric IQ tests, correlated negatively with childhood psychopathology, as assessed by the DSM-oriented scales of the Child Behavior Check List (CBCL). The correlations ranged between - .09 and - .15 and were mainly explained by common genetic factors. Intelligence moderated genetic and environmental effects on anxiety and negative affect, but not those on ADHD, ODD, and autism. The heritability of anxiety and negative affect was greatest in individuals with below-average intelligence. We discuss mechanisms through which this effect could arise, and we end with some recommendations for future research.

How a general vulnerability for psychopathology during adolescence manifests in young adults' daily lives.

BACKGROUND: There is widespread interest in the general factor of psychopathology or 'p factor', which has been proposed to reflect vulnerability to psychopathology. We examined to what extent this 'vulnerability' is associated with dysregulations in affect and behavior that occur in daily life. As such we hoped to provide an account of how this vulnerability may be maintained. METHODS: We used data from the Tracking Adolescents' Individual Lives Survey (TRAILS; N = 2,772) collected at ages 11, 14, 16, 19, and 22 years to fit a bifactor model with a general psychopathology factor, alongside internalizing, externalizing (EXT), attention-deficit/hyperactivity, and autism spectrum problem domains. Following the fifth TRAILS assessment, a subsample of participants (n = 133, age = 22.6, 43% women) with heightened risk for psychopathology completed a 6-month daily diary protocol with one assessment each day. Using a dynamic structural equation approach, we examined to what extent mean intensity, variability, inertia, and within-day co-occurrence of EXT, anxious-tense, and depressed-withdrawn affects and behaviors were associated with general factor scores. RESULTS: Unexpectedly, higher general factor scores were not associated with higher mean intensity of any of the three types of daily negative affects and behaviors, but were associated with higher variability and less carryover (inertia) EXT affects and behaviors. CONCLUSIONS: We showed that individual differences in general factor scores do not manifest as differences in average levels of daily affects and behaviors, but instead were related to a type of EXT reactivity to the environment. Future research is necessary to investigate whether reactive irritable moods may be involved in or signal vulnerability sustained psychopathology.

Distal-to-proximal etiologically relevant variables associated with the general (p) and specific factors of psychopathology.

BACKGROUND: The general factor of psychopathology, often denoted as p, captures the common variance among a broad range of psychiatric symptoms. Specific factors are co-modeled based on subsets of closely related symptoms. This paper investigated the extent to which wide-ranging genetic, personal, and environmental etiologically relevant variables are associated with p and specific psychopathology factors. METHODS: Using data from four waves (ages 11-19) of TRAILS, we modeled a bifactor model of p and four specific factors [internalizing, externalizing, ADHD, Autism Spectrum Disorder (ASD)]. Next, we examined the associations of 19 etiologically relevant variables with these psychology factors using path models that organized the variables according to the distal-to-proximal risk principle. RESULTS: Collectively, the etiologically relevant factors, including temperament traits, accounted for 55% of p's variance, 46% in ADHD, 35% in externalizing, 19% in internalizing, and 7% in ASD. The low 7% is due to insufficient unique variance in ASD indicators that load more strongly on p. Excluding temperament, variables accounted for 29% variance in p, 9% ADHD, 14% EXT, 7% INT, and 4% ASD. Most etiologically relevant factors were generic, predicting p. In addition, we identified effects on specific factors in addition to effects on p (e.g., parental SES, executive functioning); only effects on specific factors (e.g., parental rejection); opposite effects on different factors [e.g., diurnal cortisol (high INT but low EXT, p); developmental delay (high ASD and p but low EXT)]. Frustration, family functioning, parental psychopathology, executive functioning, and fearfulness had strong effects on p. CONCLUSIONS: (1) Strong generic effects on p suggest that etiologically relevant factors and psychopathology tend to cluster in persons. (2) While many factors predict p, additional as well as opposite effects on specific factors indicate the relevance of specific psychopathology factors in understanding mental disorder. (3) High frustration, neurodevelopmental problems, and a disadvantaged family environment primarily characterize p.

Patterns of sub-optimal change following CBT for childhood anxiety.

BACKGROUND: Children and adolescents demonstrate diverse patterns of symptom change and disorder remission following cognitive behavioural therapy (CBT) for anxiety disorders. To better understand children who respond sub-optimally to CBT, this study investigated youths (N = 1,483) who continued to meet criteria for one or more clinical anxiety diagnosis immediately following treatment or at any point during the 12 months following treatment. METHODS: Data were collected from 10 clinical sites with assessments at pre-and post-treatment and at least once more at 3, 6 or 12-month follow-up. Participants were assigned to one of three groups based on diagnostic status for youths who: (a) retained an anxiety diagnosis from post to end point (minimal responders); (b) remitted anxiety diagnoses at post but relapsed by end point (relapsed responders); and (c) retained a diagnosis at post but remitted to be diagnosis free at end point (delayed responders). Growth curve models assessed patterns of change over time for the three groups and examined predictors associated with these patterns including demographic, clinical and parental factors, as well as treatment factors. RESULTS: Higher primary disorder severity, being older, having a greater number of anxiety disorders, having social anxiety disorder, as well as higher maternal psychopathology differentiated the minimal responders from the delayed and relapsed responders at the baseline. Results from the growth curve models showed that severity of the primary disorder and treatment modality differentiated patterns of linear change only. Higher severity was associated with significantly less improvement over time for the minimal and relapsed response groups, as was receiving group CBT, when compared to the delayed response group. CONCLUSIONS: Sub-optimal response patterns can be partially differentiated using variables assessed at pre-treatment. Increased understanding of different patterns of change following treatment may provide direction for clinical decision-making and for tailoring treatments to specific groups of clinically anxious youth. Future research may benefit from assessing progress during treatment to detect emerging response patterns earlier.

Somatic burden of attention-deficit/hyperactivity disorder across the lifecourse.

OBJECTIVE: A thorough and comprehensive knowledge base on the extent of comorbidity of attention-deficit/hyperactivity disorder (ADHD) and somatic conditions is needed. METHOD: We compared the prevalence of a wide range of somatic conditions in individuals with and without ADHD and described sex and lifecourse differences. Individuals with an ADHD diagnosis (N = 87,394) and age and sex-matched individuals without an ADHD diagnosis were identified from a large health claims dataset representative of the general German population, including both primary and specialized care (N = 4.874,754). Results were provided for the full sample as well as stratified for sex and age (<12 years, 13-17 years, 18-29 years, 30-59 years, ≥60 years). RESULTS: The results showed that ADHD is associated with a wide variety of somatic conditions across the entire lifecourse. Specifically neurological disorders such as Parkison's disease (odds ratio [OR]: 5.21) and dementia (OR: 2.23), sleep-related disorders (OR: 2.38) and autoimmune disorders affecting the musculoskeletal, digestive, and endocrine system (fibromyalgia OR: 3.33; lupus OR: 2.17) are strongly and significantly associated with ADHD. Additionally, ADHD is associated with higher occurrence of common acute diseases typically treated by the general practitioner, hinting at an overall general lower health status. Sex differences in somatic comorbidity were not prominent. Age differences, in contrast, stood out: in particular endocrine, cardiovascular, and neurological disorders had an early onset in individuals with compared to individuals without ADHD. CONCLUSION: This research underlines the high burden of disease due to somatic conditions among individuals with ADHD. The findings indicate the need for preventive measures to reduce comorbidity.

The Mood and Resilience in Offspring (MARIO) project: a longitudinal cohort study among offspring of parents with and without a mood disorder.

BACKGROUND: One of the most robust risk factors for developing a mood disorder is having a parent with a mood disorder. Unfortunately, mechanisms explaining the transmission of mood disorders from one generation to the next remain largely elusive. Since timely intervention is associated with a better outcome and prognosis, early detection of intergenerational transmission of mood disorders is of paramount importance. Here, we describe the design of the Mood and Resilience in Offspring (MARIO) cohort study in which we investigate: 1. differences in clinical, biological and environmental (e.g., psychosocial factors, substance use or stressful life events) risk and resilience factors in children of parents with and without mood disorders, and 2. mechanisms of intergenerational transmission of mood disorders via clinical, biological and environmental risk and resilience factors. METHODS: MARIO is an observational, longitudinal cohort study that aims to include 450 offspring of parents with a mood disorder (uni- or bipolar mood disorders) and 100-150 offspring of parents without a mood disorder aged 10-25 years. Power analyses indicate that this sample size is sufficient to detect small to medium sized effects. Offspring are recruited via existing Dutch studies involving patients with a mood disorder and healthy controls, for which detailed clinical, environmental and biological data of the index-parent (i.e., the initially identified parent with or without a mood disorder) is available. Over a period of three years, four assessments will take place, in which extensive clinical, biological and environmental data and data on risk and resilience are collected through e.g., blood sampling, face-to-face interviews, online questionnaires, actigraphy and Experience Sampling Method assessment. For co-parents, information on demographics, mental disorder status and a DNA-sample are collected. DISCUSSION: The MARIO cohort study is a large longitudinal cohort study among offspring of parents with and without mood disorders. A unique aspect is the collection of granular data on clinical, biological and environmental risk and resilience factors in offspring, in addition to available parental data on many similar factors. We aim to investigate the mechanisms underlying intergenerational transmission of mood disorders, which will ultimately lead to better outcomes for offspring at high familial risk.

Genomics Research of Lifetime Depression in the Netherlands: The BIObanks Netherlands Internet Collaboration (BIONIC) Project.

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.

Psychiatric comorbidities in women with cardiometabolic conditions with and without ADHD: a population-based study.

BACKGROUND: Leveraging a large nationwide study of Icelandic women, we aimed to narrow the evidence gap around female attention-deficit/hyperactivity disorder (ADHD) and cardiometabolic comorbidities by determining the prevalence of obesity, hypertension, type 2 diabetes, and cardiovascular diseases among women with ADHD and examine the association between cardiometabolic conditions and co-occurring ADHD with anxiety and mood disorders, alcoholism/substance use disorder (SUD), self-harm, and suicide attempts. METHODS: We conducted a cross-sectional analysis of the nationwide, all-female, population-based SAGA Cohort Study (n = 26,668). To ascertain diagnoses and symptoms, we used self-reported history of ADHD diagnoses, selected cardiometabolic conditions and psychiatric disorders, and measured current depressive, anxiety, and PTSD symptoms through appropriate questionnaires (PHQ-9, GAD-7, and PCL-5). We calculated age-adjusted prevalences of cardiometabolic conditions by women's ADHD status and estimated adjusted prevalence ratios (PR) and 95% confidence intervals (CI), using modified Poisson regression models. Similarly, we assessed the association of cardiometabolic conditions and co-occurring ADHD with current psychiatric symptoms and psychiatric disorders, using adjusted PRs and 95% CIs. RESULTS: We identified 2299 (8.6%) women with a history of ADHD diagnosis. The age-adjusted prevalence of having at least one cardiometabolic condition was higher among women with ADHD (49.5%) than those without (41.7%), (PR = 1.19, 95% CI 1.14-1.25), with higher prevalence of all measured cardiometabolic conditions (myocardial infarctions (PR = 2.53, 95% CI 1.83--3.49), type 2 diabetes (PR = 2.08, 95% CI 1.66-2.61), hypertension (PR = 1.23, 95% CI 1.12-1.34), and obesity (PR = 1.18, 95% CI 1.11-1.25)). Women with cardiometabolic conditions and co-occurring ADHD had, compared with those without ADHD, substantially increased prevalence of (a) all measured mood and anxiety disorders, e.g., depression (PR = 2.38, 95% CI 2.19-2.58), bipolar disorder (PR = 4.81, 95% CI 3.65-6.35), posttraumatic stress disorder (PR = 2.78, 95% CI 2.52-3.07), social phobia (PR = 2.96, 95% CI 2.64-3.32); (b) moderate/severe depressive, anxiety, and PTSD symptoms with PR = 1.76 (95% CI 1.67-1.85), PR = 1.97 (95% CI 1.82-2.12), and PR = 2.01 (95% CI 1.88-2.15), respectively; (c) alcoholism/SUD, PR = 4.79 (95% CI 3.90-5.89); and (d) self-harm, PR = 1.47 (95% CI 1.29-1.67) and suicide attempts, PR = 2.37 (95% CI 2.05-2.73). CONCLUSIONS: ADHD is overrepresented among women with cardiometabolic conditions and contributes substantially to other psychiatric comorbidities among women with cardiometabolic conditions.

Familial co-aggregation and shared genetics of cardiometabolic disorders and traits: data from the multi-generational Lifelines Cohort Study.

BACKGROUND: It is unclear to what extent genetics explain the familial clustering and the co-occurrence of distinct cardiometabolic disorders in the general population. We therefore aimed to quantify the familial (co-)aggregation of various cardiometabolic disorders and to estimate the heritability of cardiometabolic traits and their genetic correlations using the large, multi-generational Lifelines Cohort Study. METHODS: We used baseline data of 162,416 participants from Lifelines. Cardiometabolic disorders including type 2 diabetes (T2D), cardiovascular diseases, hypertension, obesity, hypercholesterolemia, and metabolic syndrome (MetS), were defined in adult participants. Fifteen additional cardiometabolic traits indexing obesity, blood pressure, inflammation, glucose regulation, and lipid levels were measured in all included participants. Recurrence risk ratios (λR) for first-degree relatives (FDR) indexed familial (co-)aggregation of cardiometabolic disorders using modified conditional Cox proportional hazards models and were compared to those of spouses. Heritability (h2), shared environment, and genetic correlation (rg) were estimated using restricted maximum likelihood variance decomposition methods, adjusted for age, age2, and sex. RESULTS: Individuals with a first-degree relative with a cardiometabolic disorder had a higher risk of the same disorder, ranging from λFDR of 1.23 (95% CI 1.20-1.25) for hypertension to λFDR of 2.48 (95% CI 2.15-2.86) for T2D. Most of these were higher than in spouses (λSpouses < λFDR), except for obesity which was slightly higher in spouses. We found moderate heritability for cardiometabolic traits (from h2CRP: 0.26 to h2HDL: 0.50). Cardiometabolic disorders showed positive familial co-aggregation, particularly between T2D, MetS, and obesity (from λFDR obesity-MetS: 1.28 (95% CI 1.24-1.32) to λFDR MetS-T2D: 1.61 (95% CI 1.52-1.70)), consistent with the genetic correlations between continuous intermediate traits (ranging from rg HDL-Triglycerides: - 0.53 to rg LDL-Apolipoprotein B: 0.94). CONCLUSIONS: There is positive familial (co-)aggregation of cardiometabolic disorder, moderate heritability of intermediate traits, and moderate genetic correlations between traits. These results indicate that shared genetics and common genetic architecture contribute to cardiometabolic disease.

Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis.

Despite the substantial heritability of antisocial behavior (ASB), specific genetic variants robustly associated with the trait have not been identified. The present study by the Broad Antisocial Behavior Consortium (BroadABC) meta-analyzed data from 28 discovery samples (N = 85,359) and five independent replication samples (N = 8058) with genotypic data and broad measures of ASB. We identified the first significant genetic associations with broad ASB, involving common intronic variants in the forkhead box protein P2 (FOXP2) gene (lead SNP rs12536335, p = 6.32 × 10-10). Furthermore, we observed intronic variation in Foxp2 and one of its targets (Cntnap2) distinguishing a mouse model of pathological aggression (BALB/cJ strain) from controls (BALB/cByJ strain). Polygenic risk score (PRS) analyses in independent samples revealed that the genetic risk for ASB was associated with several antisocial outcomes across the lifespan, including diagnosis of conduct disorder, official criminal convictions, and trajectories of antisocial development. We found substantial genetic correlations of ASB with mental health (depression rg = 0.63, insomnia rg = 0.47), physical health (overweight rg = 0.19, waist-to-hip ratio rg = 0.32), smoking (rg = 0.54), cognitive ability (intelligence rg = -0.40), educational attainment (years of schooling rg = -0.46) and reproductive traits (age at first birth rg = -0.58, father's age at death rg = -0.54). Our findings provide a starting point toward identifying critical biosocial risk mechanisms for the development of ASB.

Impact of trajectories of maternal postpartum depression on infants' socioemotional development.

BACKGROUND: We assessed (a) the effects of postpartum depression (PPD) trajectories until 6 months postpartum on infants' socioemotional development (SED) at age 12 months, and (b) the mediating role of maternal self-efficacy (MSE), and the additional effect of postpartum anxiety at age 12 months. METHODS: We used data from POST-UP trial (n = 1843). PPD was assessed using the Edinburgh Postnatal Depression Scale (EPDS) at 1, 3, and 6 months. Infants' SED was assessed at 12 months using the Ages and Stages Questionnaire-Social-Emotional (ASQ-SE). Structural equations were applied to estimate the effect of PPD trajectories on infants' SED and mediation by MSE. The additional effects of postpartum anxiety were assessed with conditional regression. RESULTS: Higher levels of PPD over time were associated with a lower SED (coefficient for log-EPDS 3.5, 95% confidence interval 2.8; 4.2, e.g., an increase in the EPDS score from 9 to 13 worsens the ASQ-SE by 1.3 points). About half of this relationship was mediated by MSE. Postpartum anxiety had an independent adverse effect on SED. CONCLUSIONS: PPD and postpartum anxiety have a negative impact on infants' SED. MSE as a mediator may be a potential target for preventive interventions to alleviate the negative effects of maternal psychopathology on infants' SED. IMPACT: The trajectories of postpartum depression (PPD) from 1 month to 6 months were negatively related to infants' socioemotional development (SED) at age 12 months, underlining the importance of repeated assessment of PPD. Maternal self-efficacy (MSE) mediated the association between PPD and SED, implying MSE could be a potential target for preventive interventions. An additional independent negative effect of postpartum anxiety was identified, implying the assessment of postpartum anxiety also has a surplus value to identify mothers at risk.

Risk of accidents and unintentional injuries in men and women with attention deficit hyperactivity disorder across the adult lifespan.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is associated with risk-taking behavior, leading to accidents and unintentional injuries (summarized here as incidents). Main aim of this study is to determine if men and women with and without ADHD differ in the risk of mild (treated outpatient) and severe (treated inpatient) incidents across the adult lifespan (age groups: 18-29; 30-59, and ≥60 years). Secondary aim: investigate the role of comorbid mental disorders and drugs for the treatment of these comorbidities, and ADHD-medication. METHODS: Using anonymized German claims data (N = 4,575,027), adults with ADHD diagnosis during 2016-2019 (N = 17,041) were compared with a 1:4 age and sex-matched group without ADHD diagnosis. Regression analyses statistically tested group differences. RESULTS: Incidents occur in a U-shaped form across the adult lifespan. Individuals with ADHD show the same pattern but at a substantially increased risk of both mild and severe incidents throughout the lifespan. Women without ADHD are at lower risk in young adulthood than men but at higher risk in older adulthood. Women with ADHD show the same pattern for severe incidents, but for mild incidents they have the highest risk throughout the lifespan. Co-occurring anxiety disorder and the use of psycholeptics and ADHD-medication decreased the incident risk. CONCLUSION: We extend available knowledge which has hitherto focused on young adult males and traffic accidents. ADHD is associated with increased incidents across the adult lifespan, with distinct patterns regarding age, sex, and incident severity. An accurate diagnosis of ADHD in adulthood provides the first step towards prevention of accidents and unintentional injuries.

Longitudinal effects of environmental noise and air pollution exposure on autism spectrum disorder and attention-deficit/hyperactivity disorder during adolescence and early adulthood: The TRAILS study.

BACKGROUND: Exposure to ambient noise and air pollution may affect the manifestation and severity of Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD). However, evidence is limited, and most studies solely assessed environmental exposures during pregnancy and early childhood. OBJECTIVE: To examine the longitudinal effects of ambient noise and air pollutants on ASD and ADHD symptom severity during adolescence and early adulthood. METHODS: Using a longitudinal design, we included 2750 children between 10 and 12 years old from the TRacking Adolescents' Individual Lives Survey (TRAILS) in the Netherlands, who were assessed in 6 waves from 2001 to 2017. ASD was measured by the Children's Social Behavior Questionnaire and the Adult Social Behavior Questionnaire. ADHD was measured by Child Behavior Checklist and the Adult Behavior Checklist. Ambient noise and air pollution exposures, including Ozone (O3), soot, sulfur dioxide (SO2), nitrogen dioxide (NO2), particulate matter 2.5 (PM2.5), and PM10 were modeled at the residential level according to standardized protocols. The longitudinal associations between exposures and symptom outcomes were examined using linear mixed models. RESULTS: We found evidence that higher levels of exposure to PM were associated with more severe ASD and ADHD symptoms. This association decreased over time. We did not observe any other consistent associations of noise or other air pollutants with ASD and ADHD severity. CONCLUSION: The current study provides evidence for the negative impact of PM on ASD and ADHD symptoms. We did not find evidence of the negative health impact of other air pollutants and noise exposures on ASD or ADHD symptoms. Our study adds more evidence on the presence of associations between PM air pollution and neurodevelopmental diseases among adolescents and young adults.

Interplay between genetic risk and the parent environment in adolescence and substance use in young adulthood: A TRAILS study.

Many adolescents start using tobacco, alcohol, and cannabis. Genetic vulnerability, parent characteristics in young adolescence, and interaction (GxE) and correlation (rGE) between these factors could contribute to the development of substance use. Using prospective data from the TRacking Adolescent Individuals' Lives Survey (TRAILS; N = 1,645), we model latent parent characteristics in young adolescence to predict young adult substance use. Polygenic scores (PGS) are created based on genome-wide association studies (GWAS) for smoking, alcohol use, and cannabis use. Using structural equation modeling we model the direct, GxE, and rGE effects of parent factors and PGS on young adult smoking, alcohol use, and cannabis initiation. The PGS, parental involvement, parental substance use, and parent-child relationship quality predicted smoking. There was GxE such that the PGS amplified the effect of parental substance use on smoking. There was rGE between all parent factors and the smoking PGS. Alcohol use was not predicted by genetic or parent factors, nor by interplay. Cannabis initiation was predicted by the PGS and parental substance use, but there was no GxE or rGE. Genetic risk and parent factors are important predictors of substance use and show GxE and rGE in smoking. These findings can act as a starting point for identifying people at risk.

Weighing psychosocial factors in relatives for the risk of psychopathology: a study of patients with depressive and anxiety disorders and their siblings.

PURPOSE: Siblings of probands with depressive and anxiety disorders are at increased risk for psychopathology, but little is known about how risk factors operate within families to increase psychopathology for siblings. We examined the additional impact of psychosocial risk factors in probands-on top of or in combination with those in siblings-on depressive/anxious psychopathology in siblings. METHODS: The sample included 636 participants (Mage = 49.7; 62.4% female) from 256 families, each including a proband with lifetime depressive and/or anxiety disorders and their sibling(s) (N = 380 proband-sibling pairs). Sixteen psychosocial risk factors were tested. In siblings, depressive and anxiety disorders were determined with standardized psychiatric interviews; symptom severity was measured using self-report questionnaires. Analyses were performed with mixed-effects models accounting for familial structure. RESULTS: In siblings, various psychosocial risk factors (female gender, low income, childhood trauma, poor parental bonding, being single, smoking, hazardous alcohol use) were associated with higher symptomatology and likelihood of disorder. The presence of the same risk factor in probands was independently associated (low income, being single) with higher symptomatology in siblings or moderated (low education, childhood trauma, hazardous alcohol use)-by reducing its strength-the association between the risk factor and symptomatology in siblings. There was no additional impact of risk factors in probands on likelihood of disorder in siblings. CONCLUSION: Our findings demonstrate the importance of weighing psychosocial risk factors within a family context, as it may provide relevant information on the risk of affective psychopathology for individuals.

Polygenic risk for aggressive behavior from late childhood through early adulthood.

Twin studies suggest a substantial role for genes in explaining individual differences in aggressive behavior across development. It is unclear, however, how directly measured genetic risk is associated with aggressive behavior at different moments across adolescence and how genes might distinguish developmental trajectories of aggressive behavior. Here, a polygenic risk score derived from the EAGLE-Consortium genome-wide association study of aggressive behavior in children was tested as predictor of latent growth classes derived from those measures in an adolescent population (n = 2229, of which n = 1246 with genetic information) and a high-risk sample (n = 543, of which n = 335 with genetic information). In the population sample, the polygenic risk score explained variation in parent-reported aggressive behavior at all ages and distinguished between stable low aggressive behavior and moderate and high-decreasing trajectories based on parent-report. In contrast, the polygenic risk score was not associated with self- and teacher-reported aggressive behavior, and no associations were found in the high-risk sample. This pattern of results suggests that methodological choices made in genome-wide association studies impact the predictive strength of polygenic risk scores, not just with respect to power but likely also in terms of generalizability and specificity.

Educational level, attention problems, and externalizing behaviour in adolescence and early adulthood: the role of social causation and health-related selection-the TRAILS study.

Social causation and health-related selection may contribute to educational differences in adolescents' attention problems and externalizing behaviour. The social causation hypothesis posits that the social environment influences adolescents' mental health. Conversely, the health-related selection hypothesis proposes that poor mental health predicts lower educational attainment. From past studies it is unclear which of these mechanisms predominates, as attention problems and externalizing behaviour have the potential to interfere with educational attainment, but may also be affected by differences in the educational context. Furthermore, educational gradients in mental health may reflect the impact of 'third variables' already present in childhood, such as parental socioeconomic status (SES), and IQ. We investigated both hypotheses in relation to educational differences in externalizing behaviour and attention problems throughout adolescence and young adulthood. We used data from a Dutch cohort (TRAILS Study; n = 2229), including five measurements of educational level, externalizing behaviour, and attention problems from around age 14-26 years. First, we evaluated the directionality in longitudinal associations between education, externalizing behaviour, and attention problems with and without adjusting for individual differences using fixed effects. Second, we assessed the role of IQ and parental SES in relation to attention problems, externalizing behaviour, and educational level. Attention problems predicted decreases in education throughout all of adolescence and young adulthood. Differences in parental SES contributed to increases in externalizing behaviour amongst the lower educational tracks in mid-adolescence. Childhood IQ and parental SES strongly predicted education around age 14. Parental SES, but not IQ, also predicted early adolescent attention problems and externalizing behaviour. Our results provide support for the health-related selection hypothesis in relation to attention problems and educational attainment. Further, our results highlight the role of social causation from parental SES in determining adolescent educational level, attention problems, and externalizing behaviour.

Parental rejection in early adolescence predicts a persistent ADHD symptom trajectory across adolescence.

Despite a general decrease of attention-deficit/hyperactivity disorder (ADHD) symptoms during adolescence, these may persist in some individuals but not in others. Prior cross-sectional studies have shown that parenting style and their interaction with candidate genes are associated with ADHD symptoms. However, there is a lack of longitudinal research examining the independent and interactive effects of parenting and plasticity genes in predicting the course of attention-deficit/hyperactivity disorder (ADHD) symptoms across adolescence. Here, we investigated how children perceived their parents' parenting style (i.e., rejection, overprotection, and emotional warmth) at the age of 11, and their interaction with DRD4, MAOA, and 5-HTTLPR genotypes on parent-reported ADHD symptoms at three time points (mean ages 11.1, 13.4, and 16.2 years) in 1730 adolescents from the TRacking Adolescents' Individual Lives Survey (TRAILS). Growth Mixture Modeling in Mplus identified four ADHD symptom trajectories: low, moderate stable, high decreasing, and high persistent. Perceived parental rejection predicted class membership in the high persistent trajectory compared to the other classes (p < 0.001, odds ratios between 2.14 and 3.74). Gene-environment interactions were not significantly related to class membership. Our results indicate a role of perceived parental rejection in the persistence of ADHD symptoms. Perceived parental rejection should, therefore, be taken into consideration during prevention and treatment of ADHD in young adolescents.

Cognitive Task Performance and Subjective Cognitive Symptoms in Individuals With Chronic Fatigue Syndrome or Fibromyalgia: A Cross-Sectional Analysis of the Lifelines Cohort Study.

OBJECTIVE: This study examined cognitive task performance and self-reported cognitive functioning in individuals with chronic fatigue syndrome (CFS) and fibromyalgia (FM) in a population-based sample and investigated the role of mood and anxiety disorders as well as severity of the physical symptoms. METHODS: This study was performed in 79,966 participants (mean [standard deviation] age = 52.9 [12.6] years, 59.2% women) from the Lifelines general population. Symptoms consistent with the diagnostic criteria for CFS and FM were assessed using questionnaires. Two comparison groups were used: participants with self-reported medical disorders with well-defined pathophysiology (i.e., multiple sclerosis and rheumatic arthritis) and controls without these diseases. Objective task performance was based on the computerized CogState cognitive battery and subjective cognitive symptoms using the concentration subscale of the Checklist Individual Strength. RESULTS: Cognitive task performance was poorer in individuals with CFS versus controls without disease and controls with a medical disorder, although the severity of cognitive dysfunction was mild. Participants meeting the criteria for CFS ( n = 2461) or FM ( n = 4295) reported more subjective cognitive symptoms compared with controls without a medical disorder ( d = 1.53, 95% confidence interval [CI] = 1.49-1.57 for CFS; d = 1.25, 95% CI = 1.22-1.29 for FM) and participants with a medical disease ( d = 0.62, 95% CI = 0.46-0.79 for CFS; d = 0.75, 95% CI = 0.70-0.80 for FM). These differences remained essentially the same when excluding participants with comorbid mood or anxiety disorders or adjusting for physical symptom severity. CONCLUSIONS: Subjective cognitive symptoms and, to a lesser extent, suboptimal cognitive task performance are more prevalent in individuals with CFS or FM compared with controls without these conditions.

Familial risk for depressive and anxiety disorders: associations with genetic, clinical, and psychosocial vulnerabilities.

BACKGROUND: In research and clinical practice, familial risk for depression and anxiety is often constructed as a simple Yes/No dichotomous family history (FH) indicator. However, this measure may not fully capture the liability to these conditions. This study investigated whether a continuous familial loading score (FLS), incorporating family- and disorder-specific characteristics (e.g. family size, prevalence of depression/anxiety), (i) is associated with a polygenic risk score (PRS) for major depression and with clinical/psychosocial vulnerabilities and (ii) still captures variation in clinical/psychosocial vulnerabilities after information on FH has been taken into account. METHODS: Data came from 1425 participants with lifetime depression and/or anxiety from the Netherlands Study of Depression and Anxiety. The Family Tree Inventory was used to determine FLS/FH indicators for depression and/or anxiety. RESULTS: Persons with higher FLS had higher PRS for major depression, more severe depression and anxiety symptoms, higher disease burden, younger age of onset, and more neuroticism, rumination, and childhood trauma. Among these variables, FH was not associated with PRS, severity of symptoms, and neuroticism. After regression out the effect of FH from the FLS, the resulting residualized measure of FLS was still associated with severity of symptoms of depression and anxiety, rumination, and childhood trauma. CONCLUSIONS: Familial risk for depression and anxiety deserves clinical attention due to its associated genetic vulnerability and more unfavorable disease profile, and seems to be better captured by a continuous score that incorporates family- and disorder-specific characteristics than by a dichotomous FH measure.