Search

The set of methods discussed in this collection has emerged from the convergence of two scientific fields-genetics and causal inference. In this introduction, we discuss relevant aspects of each field and show how their convergence arises from the natural experiments that genetics offer. We present introductory concepts useful to readers unfamiliar with genetically informed methods for causal inference. We conclude that existing applications and foreseeable developments should ensure that we rapidly reap the rewards of this relatively new field, not only in terms of our understanding of human disease and development, but also in terms of tangible translational applications.

Polygenic scores (PGS) are now commonly available in longitudinal cohort studies, leading to their integration into epidemiological research. In this work, our aim is to explore how polygenic scores can be used as exposures in causal inference-based methods, specifically mediation analyses. We propose to estimate the extent to which the association of a polygenic score indexing genetic liability to an outcome could be mitigated by a potential intervention on a mediator. To do this this, we use the interventional disparity measure approach, which allows us to compare the adjusted total effect of an exposure on an outcome, with the association that would remain had we intervened on a potentially modifiable mediator. As an example, we analyse data from two UK cohorts, the Millennium Cohort Study (MCS, N = 2575) and the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 3347). In both, the exposure is genetic liability for obesity (indicated by a PGS for BMI), the outcome is late childhood/early adolescent BMI, and the mediator and potential intervention target is physical activity, measured between exposure and outcome. Our results suggest that a potential intervention on child physical activity can mitigate some of the genetic liability for childhood obesity. We propose that including PGSs in a health disparity measure approach, and causal inference-based methods more broadly, is a valuable addition to the study of gene-environment interplay in complex health outcomes.

Identifying mechanisms underlying the intergenerational transmission of risk for attention-deficit/hyperactivity disorder (ADHD) traits can inform interventions and provide insights into the role of parents in shaping their children’s outcomes. We investigated whether genetic transmission and genetic nurture (environmentally mediated effects) underlie associations between polygenic scores indexing parental risk and protective factors and their offspring’s ADHD traits. This birth cohort study included 19,506 genotyped mother-father-offspring trios from the Norwegian Mother, Father and Child Cohort Study. Polygenic scores were calculated for parental factors previously associated with ADHD, including psychopathology, substance use, neuroticism, educational attainment, and cognitive performance. Mothers reported on their 8-year-old children’s ADHD traits (n = 9,454 children) using the Parent/Teacher Rating Scale for Disruptive Behaviour Disorders. We found that associations between ADHD maternal and paternal polygenic scores and child ADHD traits decreased significantly when adjusting for the child polygenic score (pΔβ = 9.95 × 10−17 for maternal and pΔβ = 1.48 × 10−14 for paternal estimates), suggesting genetic transmission of ADHD risk. Similar patterns suggesting genetic transmission of risk were observed for smoking, educational attainment, and cognition. The maternal polygenic score for neuroticism remained associated with children’s ADHD ratings even after adjusting for the child polygenic score, indicating genetic nurture. There was no robust evidence of genetic nurture for other parental factors. Our findings indicate that the intergenerational transmission of risk for ADHD traits is largely explained by the transmission of genetic variants from parents to offspring rather than by genetic nurture. Observational associations between parental factors and childhood ADHD outcomes should not be interpreted as evidence for predominantly environmentally mediated effects.

Previous genetically informed studies have uncovered likely causal relationships between mental health problems and self-harm but resulting causal estimates may be biased due to unmediated pleiotropy. By fitting Mendelian Randomization - Direction of Causation (MR-DoC) models that explicitly model pleiotropy, we investigated the effect of four quantitatively measured mental health problems - major depressive disorder (MDD), schizophrenia, attention-deficit hyperactivity disorder (ADHD), and insomnia, on non-suicidal self-harm (NSSH) and suicidal self-harm (SSH), separately. We used data of 12,723 twins (56.6% females) in the Twins Early Development Study. Besides substantial pleiotropy, we found effects from child-rated depressive symptoms to both NSSH (β = 0.194, 95% CIs: 0.131, 0.257) and SSH (β = 0.210, 95% CIs: 0.125, 0.295). Similarly, effects flowed from parent-rated depressive symptoms to NSSH (β = 0.092, 95% CIs: 0.004, 0.181) and SSH (β = 0.165, 95% CIs: 0.051, 0.281). We did not find evidence of aetiological difference between NSSH and SSH.

Bullying victimisation is a prevalent stressor associated with serious health problems. To inform intervention strategies, it is important to understand children’s patterns of involvement in bullying victimisation and perpetration across development, and identify early risk factors for these developmental trajectories. We analysed data from the Millennium Cohort Study (N = 14,525; 48.6% female, 82.6% White), a representative birth cohort of British children born in 2000–2002 across the UK. Bullying victimisation and perpetration were assessed via child, mother, and teacher reports at ages 5, 7, 11, and 14 years. Early risk factors (child emotional, cognitive, and physical vulnerabilities, and adverse family environments) were assessed at ages 9 months, 3, and 5 years. Using k-means for longitudinal data, we identified five joint trajectories of victimisation and perpetration across ages 5, 7, 11, and 14: uninvolved children (59.78%), early child victims (9.96%), early adolescent victims (15.07%), early child bullies (8.01%), and bully- victims (7.19%). Individual vulnerabilities (e.g., emotional dysregulation, cognitive difficulties) and adverse family environments (maternal psychopathology, low income) in pre-school years independently forecast multiple trajectories of bullying involvement. Compared to victims, bully-victims were more likely to be male, have cognitive difficulties, and experience harsh discipline and low income. Interventions addressing these risk factors (e.g., via accessible mental health care, stigma-based interventions, or programs to support low-income families) may help to prevent bullying involvement and its associated sequelae.

Conduct problems in children and adolescents affect individuals, families, and their environment. The aetiology of conduct problems involves a combination of genetic and environmental risk factors, many of which are inherently linked to parental characteristics given parents’ central role in children’s lives across development. It is important to disentangle to what extent links between parental characteristics and children’s behaviour are due to transmission of genetic risk or due to environmentally mediated genetic influences on offspring behaviour (i.e., genetic nurture). We used 31,346 genotyped mother-father-child trios from the Norwegian Mother, Father and Child Cohort Study (MoBa), testing genetic transmission and genetic nurture effects on conduct problems using 12 polygenic scores (PGS) spanning psychiatric conditions, substance use, education-related factors, and other risk factors. Among genotyped trios, maternal reports of conduct problems at age 8 years were available for 15,516 children. We found significant genetic transmission effects on conduct problems for 11 out of 12 PGS (strongest positive association: PGS for smoking, β = 0.07 95% confidence interval = [0.05, 0.08]; strongest negative association: PGS for education, β = –0.04, 95% confidence interval = [¬–0.06, –0.02]). Conversely, we did not find strong evidence for genetic nurture effects for child conduct problems using our selection of PGS. Our findings provide evidence for genetic transmission in the association between parental characteristics like psychiatric conditions or risk behaviours and child conduct problems. Our results may also indicate that genetic nurture is of limited aetiological importance for conduct problems—though effects of small magnitude or effects via parental traits not captured by the included PGS remain a possibility.

Noncognitive skills such as motivation and self-regulation, predict academic achievement beyond cognitive skills. However, the role of genetic and environmental factors and of their interplay in these developmental associations remains unclear. We provide a comprehensive account of how cognitive and noncognitive skills contribute to academic achievement from ages 7 to 16 in a sample of >10,000 children from England and Wales. Results indicated that noncognitive skills become increasingly predictive of academic achievement across development. Triangulating genetic methods, including twin analyses and polygenic scores (PGS), we found that the contribution of noncognitive genetics to academic achievement becomes stronger over development. The PGS for noncognitive skills predicted academic achievement developmentally, with prediction nearly doubling by age 16, pointing to gene-environment correlation (rGE). Within-family analyses indicated both passive and active/evocative rGE processes driven by noncognitive genetics. By studying genetic effects through a developmental lens, we provide novel insights into the role of noncognitive skills in academic development.

Analysis of secondary data sources (such as cohort studies, survey data, and administrative records) has the potential to provide answers to science and society’s most pressing questions. However, researcher biases can lead to questionable research practices in secondary data analysis, which can distort the evidence base. While pre-registration can help to protect against researcher biases, it presents challenges for secondary data analysis. In this article, we describe these challenges and propose novel solutions and alternative approaches. Proposed solutions include approaches to (1) address bias linked to prior knowledge of the data, (2) enable pre-registration of non-hypothesis-driven research, (3) help ensure that pre-registered analyses will be appropriate for the data, and (4) address difficulties arising from reduced analytic flexibility in pre-registration. For each solution, we provide guidance on implementation for researchers and data guardians. The adoption of these practices can help to protect against researcher bias in secondary data analysis, to improve the robustness of research based on existing data.

ImportanceChildren’s exposure to screen time has been associated with poor mental health outcomes, yet the role of genetic factors in this association remains largely unknown.ObjectiveWe examined (1) the longitudinal phenotypic association between child screen time and mental health outcomes and (2) the potential genetic confounding of this association. We hypothesized that genetics partially account for observed phenotypic associations.DesignLongitudinal (baseline and one-year follow-up) population-based cohort.SettingAdolescent Brain Cognitive Development, 21 sites in the United States.ParticipantsThis study included 4,262 children of genetically assigned European ancestry with mean age 9.9 years [SD = 0.6 years], 46.8% female.ExposureChildren’s daily screen time (in hours) was assessed both by child-report and parent-report questionnaires at baseline.Main Outcomes and MeasuresChild psychiatric problems, specifically attention and internalizing problems, were measured with the parent-rated Child Behavior Checklist at the one-year follow-up. We used Genetic sensitivity analyses (Gsens), based on structural equation models using polygenic risk scores (PRS) of both exposure and outcomes, and either single nucleotide polymorphism (SNP)-based heritability or twin-based heritability to estimate genetic confounding of associations between child screen time and attention or internalizing problems, separately.ResultsWe found that child screen time was positively associated with the different psychiatric problems. Further, the television time PRS was associated with child screen time (β=0.18 SD, 95% CI: 0.14, 0.23); the ADHD PRS was associated with attention problems (β=0.13 SD, 95% CI: 0.10, 0.16); and the depression PRS was associated with internalizing problems (β=0.10 SD, 95% CI: 0.07, 0.13). These PRSs were associated with cross-traits, suggesting genetic confounding. Using PRSs and SNP-based heritability, we estimated that genetic confounding entirely accounts for the association between child screen time and attention problems, and moderately (42.7%) accounts for the association between child screen time and internalizing problems. When PRSs and twin-based heritability estimates were used, genetic confounding fully explained both associations.Conclusions and RelevanceGenetic confounding may explain a substantial part of the associations between child screen time and psychiatric problems. Potential interventions to reduce screen time could be less effective in reducing psychiatric problems than previously hypothesized.

OBJECTIVE: Childhood maltreatment is associated with mental health problems, but the extent to which this relationship is causal remains unclear. To strengthen causal inference, the authors conducted a systematic review and meta-analysis of quasi-experimental studies examining the relationship between childhood maltreatment and mental health problems.METHODS: A search of PubMed, PsycINFO, and Embase was conducted for peer-reviewed, English-language articles from database inception until January 1, 2022. Studies were included if they examined the association between childhood maltreatment and mental health problems using a quasi-experimental method (e.g., twin/sibling differences design, children of twins design, adoption design, fixed-effects design, random-intercept cross-lagged panel model, natural experiment, propensity score matching, or inverse probability weighting).RESULTS: Thirty-four quasi-experimental studies were identified, comprising 54,646 independent participants. Before quasi-experimental adjustment for confounding, childhood maltreatment was moderately associated with mental health problems (Cohen's d=0.56, 95% CI=0.41, 0.71). After quasi-experimental adjustment, a small association between childhood maltreatment and mental health problems remained (Cohen's d=0.31, 95% CI=0.24, 0.37). This adjusted association between childhood maltreatment and mental health was consistent across different quasi-experimental methods, and generalized across different psychiatric disorders.CONCLUSIONS: These findings are consistent with a small, causal contribution of childhood maltreatment to mental health problems. Furthermore, the findings suggest that part of the overall risk of mental health problems in individuals exposed to maltreatment is due to wider genetic and environmental risk factors. Therefore, preventing childhood maltreatment and addressing wider psychiatric risk factors in individuals exposed to maltreatment could help to prevent psychopathology.

Background and Hypothesis Previous studies have shown a robust relationship between childhood adversity and subsequent psychotic symptoms. However, the role of familial risk factors underlying this relationship remains largely unclear. Here, we tested whether offspring childhood adversity and postnatal maternal psychopathology mediated the relationship between maternal childhood adversity and offspring psychotic experiences. Study Design N = 3068 mother-offspring dyads were included. Maternal history of childhood adversity was retrospectively assessed using the Childhood Trauma Questionnaire during pregnancy. Maternal psychopathology was assessed during and after pregnancy. Twenty-four offspring childhood adversities were assessed by maternal interview when the child was 10 years old. Offspring psychotic experiences were examined using self-report at 14 years. Structural equation mediation models were conducted to explore whether maternal postnatal psychopathology and offspring childhood adversities sequentially mediated the relationship between maternal childhood adversity and offspring psychotic experiences. Analyses were adjusted for sociodemographic confounders. Study Results Maternal history of childhood adversity was associated with offspring childhood adversities (β = 0.12, 95% CI: 0.09 to 0.16). Offspring childhood adversity mediated the association of maternal childhood adversity with offspring hallucinations (βindirect effect = 0.008, 95% CI: 0.002 to 0.014, proportion mediated = 16.3%) and delusions (βindirect effect = 0.006, 95% CI: 0.000 to 0.012, proportion mediated = 13.1%). Conclusions Intergenerational transmission of childhood adversity can be considered of relevance in the etiology of psychosis vulnerability and can potentially serve as a modifiable risk factor.

BackgroundRetrospective self-reports of childhood trauma are associated with a greater risk of psychopathology in adulthood than prospective measures of trauma. Heritable reporter characteristics are anticipated to account for part of this association, whereby genetic predisposition to certain traits influences both the likelihood of self-reporting trauma and of developing psychopathology. However, previous research has not considered how gene–environment correlation influences these associations.AimsTo investigate reporter characteristics associated with retrospective self-reports of childhood trauma and whether these associations are accounted for by gene–environment correlation.MethodIn 3963 unrelated individuals from the Twins Early Development Study, we tested whether polygenic scores for 21 psychiatric, cognitive, anthropometric and personality traits were associated with retrospectively self-reported childhood emotional and physical abuse. To assess the presence of gene–environment correlation, we investigated whether these associations remained after controlling for composite scores of environmental adversity across development.ResultsRetrospectively self-reported childhood trauma was associated with polygenic scores for autism spectrum disorder (ASD), body mass index (BMI), post-traumatic stress disorder (PTSD) and risky behaviours. When composite scores of environmental adversity were controlled for, only associations with the polygenic scores for ASD and PTSD remained significant.ConclusionsGenetic predisposition to ASD and PTSD may increase liability to experiencing or interpreting events as traumatic. Associations between genetic predisposition for risky behaviour and BMI with self-reported childhood trauma may reflect gene–environment correlation. Studies of the association between retrospectively self-reported childhood trauma and later-life outcomes should consider that genetically influenced reporter characteristics may confound associations, both directly and through gene–environment correlation.

BACKGROUND Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are two highly heritable neurodevelopmental disorders. Several lines of evidence point towards the presence of shared genetic factors underlying ASD and ADHD. We conducted genomic analyses of common risk variants (i.e. single nucleotide polymorphisms, SNPs) shared by ASD and ADHD, and those specific to each disorder. METHODS With the summary data from two GWAS, one on ASD (N = 46,350) and another on ADHD (N = 55,374) individuals, we used genomic structural equation modelling and colocalization analysis to identify SNPs shared by ASD and ADHD and SNPs specific to each disorder. Functional genomic analyses were then conducted on shared and specific common genetic variants. Finally, we performed a bidirectional Mendelian randomization analysis to test whether the shared genetic risk between ASD and ADHD was interpretable in terms of reciprocal relationships between ASD and ADHD. RESULTS We found that 37.5% of the SNPs associated with ASD (at p

While large-scale volunteer-based studies such as the UK Biobank (UKBB) have become the cornerstone of genetic epidemiology, the study participants are rarely representative of their target population.Here, we aim to evaluate the impact of non-random participation in the UKBB, and to pin down areas of research that are particularly susceptible to biases when using non-representative samples for genome-wide discovery. By comparing 14 harmonized characteristics of the UKBB participants to that of a representative sample, we derived a model for participation probability. We then conducted inverse probability weighted genome-wide association analyses (wGWA) on 19 UKBB traits. Comparing the output obtained from wGWA (Neffective=94,643 – 102,215) to standard GWA analyses (N=263,464 – 283,749), we assessed the impact of participation bias on three estimated quantities, namely 1) genotype-phenotype associations, 2) heritability and genetic correlation estimates and 3) exposure-outcome causal effect estimates obtained from Mendelian Randomization. Participation bias can lead to both overestimation (e.g., cancer, education) and underestimation (e.g., coffee intake, depression/anxiety) of SNP effects. Novel SNPs were identified in wGWA for 12 of the included traits, highlighting SNPs missed as a result of participation bias. While the impact of participation bias on heritability estimates was small (average change in h2: 1.5%, maximum: 5%), substantial distortions were present for genetic correlations (average absolute change in rg: 0.07, maximum: 0.31) and Mendelian Randomization estimates (average absolute change in standardized estimates: 0.04, maximum: 0.15), most markedly for socio-behavioural traits including education, smoking and BMI. Overall, the bias mainly affected the magnitude of effects, rather than direction. In contrast, genome-wide findings for more molecular/physical traits (e.g., LDL, SBP) exhibited less bias as a result of selective participation.Our results highlight that participation bias can distort genomic findings obtained in non-representative samples, and we propose a viable solution to reduce such bias. Moving forward, more efforts ensuring either sample representativeness or correcting for participation bias are paramount, especially when investigating the genetic underpinnings of behaviour, lifestyles and social outcomes.

The primary goal motivating the scientific field of Developmental Psychopathology is to discover why some individuals develop mental health and neuro-developmental difficulties while others do not. This is not simply a 'blue skies' preoccupation: the underlying hope, of course, is to translate such discoveries to the benefit of individuals, families and communities, reducing poor outcomes for those at risk and - in the best case scenario - ensuring that they thrive. A core tenet of the bio-psycho-social framework within which this field of enquiry operates is that children's difficulties are determined by the interplay of predisposing genetic risk and resilience factors and the environments and experiences to which individuals are exposed. From this perspective, understanding gene-environment (GE) interplay is a necessary condition for explaining and, as importantly predicting, why one individual is at risk while another is not. If we believe this, then the risk calculators designed to show who will and will not get a particular disorder - all the rage at the moment - are doomed to fail until they can go beyond modelling the main effects of genes and environments, and reliably estimate GE processes too. Despite significant progress, we remain a considerable way off cracking this problem.

Background The COVID-19 pandemic has affected all our lives, not only through the infection itself but also through the measures taken to control the spread of the virus (e.g. lockdown). Aims Here, we investigated how the COVID-19 pandemic and unprecedented lockdown affected the mental health of young adults in England and Wales. Method We compared the mental health symptoms of up to 4773 twins in their mid-20s in 2018 prior to the COVID-19 pandemic (T1) and during four-wave longitudinal data collection during the pandemic in April, July and October 2020, and in March 2021 (T2–T5) using phenotypic and genetic longitudinal designs. Results The average changes in mental health were small to medium and mainly occurred from T1 to T2 (average Cohen d = 0.14). Despite the expectation of catastrophic effects of the pandemic on mental health, we did not observe trends in worsening mental health during the pandemic (T3–T5). Young people with pre-existing mental health problems were disproportionately affected at the beginning of the pandemic, but their increased problems largely subsided as the pandemic persisted. Twin analyses indicated that the aetiology of individual differences in mental health symptoms did not change during the lockdown (average heritability 33%); the average genetic correlation between T1 and T2–T5 was 0.95, indicating that genetic effects before the pandemic were substantially correlated with genetic effects up to a year later. Conclusions We conclude that on average the mental health of young adults in England and Wales has been remarkably resilient to the effects of the pandemic and associated lockdown.

BackgroundSelf-harm is a major health concern, not only as a signal of distress but also as a strong predictor of later suicide. Self-harm can be further refined into suicidal self-harm (SSH, i.e. suicide attempt) and non-suicidal self-harm (NSSH). Understanding the aetiologies of NSSH and SSH can help inform suicide prevention strategies. Using a twin design, we investigated the phenotypic and aetiological relationships between NSSH and SSH, and their aetiological overlap with mental health problems.MethodsWe analysed data from the Twins Early Development Study using structural equation modelling. At age 21 years, 9063 twins (62.4% female) answered questions related to self-harm. At age 16 years, 19 self- or parent-reported mental health measures were administered, including measures of internalising and externalising problems, psychotic-like experiences and substance abuse.ResultsPrevalences for NSSH and SSH were 21.9% and 10.5%, respectively. Additive genetic factors explained half of the variance in NSSH (55%) and SSH (50%), with the rest explained by non-shared environmental factors. Phenotypically, NSSH and SSH were strongly correlated (r = 0.87) with their correlation explained by genetic (57%) and non-shared environmental (43%) factors. We found no evidence that NSSH and SSH differed in their phenotypic and aetiological relationships with mental health measures.ConclusionOur findings suggest no aetiological difference between NSSH and SSH. NSSH and SSH should be regarded as two different ends of a continuum, rather than as two distinct categories.

Objective Parent anxiety is associated with offspring internalizing problems (emotional problems related to anxiety and depression). This may reflect causal processes, whereby exposure to parent anxiety directly influences offspring internalizing (and/or vice versa). However, parent-offspring associations could also be attributable to their genetic relatedness. We present a systematic review and meta-analysis to investigate whether exposure to parent anxiety is associated with offspring internalizing after controlling for genetic relatedness. Method A literature search in five databases identified 429 records. Publications were retained if they used a quasi-experimental design in a general population sample to control for participant relatedness in associations between parent anxiety and offspring internalizing outcomes. Publications were excluded if they involved an experimental exposure or intervention. Studies of pre- and post-natal anxiety exposure were meta-analysed separately. Pearson’s correlation coefficient estimates (r) were pooled using multilevel random effects models. Results Eight publications were retained. Data were drawn from four population cohorts, each unique to a quasi-experimental design: adoption, sibling-comparison, children-of-twins or in-vitro-fertilisation. Cohorts were located in northern Europe or America. Families were predominantly of European ancestry. Three publications (Nfamilies>11,700; offspring aged 0.5—10 years) showed no association between prenatal anxiety exposure and offspring internalizing outcomes after accounting for participant relatedness (r=.04, CI -.07,.14). Six publications (Nfamilies>12,700; offspring aged 0.75—22 years) showed a small but significant association between concurrent symptoms in parents and offspring, after accounting for participant relatedness (r=.13, CI .04,.21). Conclusion Initial literature, derived from homogenous populations, suggests that prenatal anxiety exposure does not cause offspring internalizing outcomes. However, postnatal anxiety exposure may be causally associated with concurrent offspring internalizing, via non-genetic pathways. Longitudinal stability, child-to-parent effects, and the role of moderators and methodological biases require attention.

Background This study examined the genetic and environmental influences underlying baseline level and developmental course of callous-unemotional (CU) traits across childhood and adolescence. Methods The data on 8,958 twin pairs (3,108 MZ twin pairs and 5,850 DZ twin pairs) from the Twins Early Development Study were analysed. CU traits were assessed at ages 7, 9, 12 and 16 by mothers and analysed using a biometric latent growth model. Results Individual differences in the baseline level of CU traits were highly heritable (76.5%), while the heritability of the developmental course of CU traits was moderate (43.6%). The genetic influences on baseline level and developmental course of CU traits were mostly nonoverlapping. Nonshared environment made a modest contribution to the baseline level of CU traits (21.7%). Nonshared environmental influences on the developmental course of CU traits were moderate (43.2%), with nearly half of them being the same as those influencing the baseline level and just over half being specific. Shared environmental effects did not contribute to systematic change across childhood and adolescence but were rather age-specific. Conclusions Our findings demonstrate that rather than only being conceptualized as factors of stability, genes also play a dynamic role in explaining systematic change in CU traits. Genetic effects for the initial risk and subsequent development of CU traits are not the same. In addition to genetic factors, nonshared environmental influences play an important role in explaining why some children will increase or maintain their CU traits over time, whereas other will desist. New genetic and environmental influences with age suggest that repeated, age-tailored interventions may be required throughout development to make a lasting difference in the presentation of CU traits and associated outcomes.

Background: Theoretical models of the development of childhood externalizing disorders emphasize the role of parents. Empirical studies have not been able to identify specific aspects of parental behaviors explaining a considerable proportion of the observed individual differences in externalizing problems. The problem is complicated by the contribution of genetic factors to externalizing problems, as parents provide both genes and environments to their children. We studied the joint contributions of direct genetic effects of children and the indirect genetic effects of parents through the environment on externalizing problems. Methods: The study used genome-wide single nucleotide polymorphism data from 9,675 parent–offspring trios participating in the Norwegian Mother Father and child cohort study. Based on genomic relatedness matrices, we estimated the contribution of direct genetic effects and indirect maternal and paternal genetic effects on ADHD, conduct and disruptive behaviors at 8 years of age. Results: Models including indirect parental genetic effects were preferred for the ADHD symptoms of inattention and hyperactivity, and conduct problems, but not oppositional defiant behaviors. Direct genetic effects accounted for 11% to 24% of the variance, whereas indirect parental genetic effects accounted for 0% to 16% in ADHD symptoms and conduct problems. The correlation between direct and indirect genetic effects, or gene–environment correlations, decreased the variance with 16% and 13% for conduct and inattention problems, and increased the variance with 6% for hyperactivity problems. Conclusions: This study provides empirical support to the notion that parents have a significant role in the development of childhood externalizing behaviors. The parental contribution to decrease in variation of inattention and conduct problems by gene–environment correlations would limit the number of children reaching clinical ranges in symptoms. Not accounting for indirect parental genetic effects can lead to both positive and negative bias when identifying genetic variants for childhood externalizing behaviors. publishedVersion

Bullying victimisation is a prevalent stressor associated with serious health problems. To inform intervention strategies, it is important to understand children's patterns of involvement in bullying victimisation and perpetration across development, and identify early risk factors for these developmental trajectories. We analysed data from the Millennium Cohort Study (N = 14,525; 48.6% female, 82.6% White), a representative birth cohort of British children born in 2000-2002 across the UK. Bullying victimisation and perpetration were assessed via child, mother, and teacher reports at ages 5, 7, 11, and 14 years. Early risk factors (child emotional, cognitive, and physical vulnerabilities, and adverse family environments) were assessed at ages 9 months, 3, and 5 years. Using k-means for longitudinal data, we identified five joint trajectories of victimisation and perpetration across ages 5, 7, 11, and 14: uninvolved children (59.78%), early child victims (9.96%), early adolescent victims (15.07%), early child bullies (8.01%), and bully- victims (7.19%). Individual vulnerabilities (e.g., emotional dysregulation, cognitive difficulties) and adverse family environments (maternal psychopathology, low income) in pre-school years independently forecast multiple trajectories of bullying involvement. Compared to victims, bully-victims were more likely to be male, have cognitive difficulties, and experience harsh discipline and low income. Interventions addressing these risk factors (e.g., via accessible mental health care, stigma-based interventions, or programs to support low-income families) may help to prevent bullying involvement and its associated sequelae.

Addiction to nicotine, alcohol and cannabis commonly co-occurs, which is thought to partly stem from a common heritable liability. To elucidate its genetic architecture, we modelled the common liability to addiction, inferred from genetic correlations among six measures of dependence and frequency of use of nicotine, alcohol and cannabis. Forty-two genetic variants were identified in the multivariate genome-wide association study on the common liability to addiction, of which 67% were novel and not associated with the six phenotypes. Mapped genes highlighted the role of dopamine (e.g., dopamine D2 gene), and showed enrichment for several components of the central nervous systems (e.g., mesocorticolimbic brain regions) and molecular pathways (dopaminergic, glutamatergic, GABAergic) that are thought to modulate drug reinforcement. Genetic correlations with other traits were most prominent for reward-related behaviours (e.g., risk-taking, cocaine and heroin use) and mood (e.g., depression, insomnia). These genome-wide results triangulate and expand previous preclinical and human studies focusing on the neurobiological substrates of addiction, and help to elucidate the common genetic architecture underlying addiction.

Co-occurring national rises in online media use and mental health problems have prompted investigations into their association, although most of this literature is focussed on the deleterious effects of media exposure. We assessed phenotypic associations between media use and mental health in young adulthood (M age= 22.14) and their aetiology using multivariate twin analyses in over 4,000 twin pairs and complementary polygenic score analyses on over 6,000 genotyped unrelated individuals. Crucially we go beyond traditionally explored negative uses of online media (online victimisation and problematic internet use) to investigate diverse media uses such as posting online content and watching video clips. We also distinguish both positive (pro-social behaviour) and negative (anxiety, depression, peer and behaviour problems) mental health measures. Negative media use correlated with negative mental health outcomes (r =0.11 to 0.32), but positive media use correlated with prosocial behaviour (r = 0.20) and better mental health outcomes (r = -0.24). Both positive and negative media use were moderately heritable (ranging from 20% to 49%) and their associations with mental health were primarily due to genetic influences (44-88%). Psychiatric polygenic scores were also correlated with media use although effect sizes were small. These findings echo calls for a more nuanced investigation to media use and mental health associations given evidence that their cooccurrence can be underlined by common genetic vulnerabilities.