Abeygunawardane AI: Attention to the eyes and fear-recognition deficits in child psychopathy. Br J Psychiatry. 2006; 189:280-281. 8 Kahn RE, Frick PJ, Youngstrom E, Findling RL, Youngstrom JK: The effects of including a callous-unemotional specifier for the diagnosis of conduct disorder.

Childhood conduct problems are associated with amygdala and anterior insula hypoactivity during a complex affective processing task including an empathy component. Suppressor effects between conduct problems and callous-unemotional traits in the amygdala suggest a potential neural substrate for heterogeneity in affective profiles associated with conduct problems.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attentiondeficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.

Youth with high callous-unemotional traits (CU) are at risk for early-onset and persistent conduct problems. Research suggests that there may be different developmental pathways to CU (genetic/constitutional vs environmental), and that the absence or presence of co-occurring internalizing problems is a key marker. However, it is unclear whether such a distinction is valid. Intermediate phenotypes such as DNA methylation, an epigenetic modification regulating gene expression, may help to clarify aetiological pathways. This is the first study to examine prospective inter-relationships between environmental risk (prenatal/postnatal) and DNA methylation (birth, age 7, age 9) in the prediction of CU (age 13), for youth low vs. high in internalizing problems. We focused on DNA methylation in the vicinity of the oxytocin receptor (OXTR) gene as it has been previously implicated in CU. Participants were 84 youth with early-onset and persistent conduct problems drawn from the Avon Longitudinal Study of Parents and Children. For youth with low internalizing problems (46%), we found that: (i) OXTR methylation at birth associated with higher CU (age 13) as well as decreased experience of victimization during childhood (birth – age 9), (ii) higher prenatal parental risks (maternal psychopathology, criminal behaviors, substance use) associated with higher OXTR methylation at birth, and (iii) OXTR methylation levels were more stable across time (birth – age 9). In contrast, for youth with high internalizing problems, CU was associated with prenatal risks of an interpersonal nature (i.e., intimate partner violence, family conflict) but not OXTR methylation. Findings support the existence of distinct developmental pathways to CU.

It is unclear whether maltreatment types exert common or specific effects on mental health. In the current study, we aimed to systematically characterize the unique, shared and cumulative effects of maltreatment types on psychiatric symptoms, using data drawn from a community sample of high-risk youth (n=204, M=18.85). Analyses controlled for a range of potentially confounding variables, including socio-demographic variables, neighbourhood deprivation and levels of community violence exposure. Outcome measures included multi-informant reports of internalizing difficulties, as well as data on externalizing problems and trauma-related symptoms. We found that (i) consistent with previous studies, maltreatment types were highly interrelated and frequently co-occurred; (ii) symptom severity linearly increased with the number of maltreatment types experienced (more so for self-report vs informant ratings); and (iii) while most forms of maltreatment were significantly associated with mental health outcomes when examined individually, few unique effects were observed when modelling maltreatment types simultaneously, pointing to an important role of shared variance in driving maltreatment effects on mental health. Emotional abuse emerged as the main independent predictor of psychiatric symptomatology - over and above other maltreatment types - and this effect was comparable for males and females (i.e. no significant interaction with sex). Findings contribute to a better understanding of heterogeneity in individual responses to maltreatment.

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent developmental disorder, associated with a range of long-term impairments. Variation in DNA methylation, an epigenetic mechanism, is implicated in both neurobiological functioning and psychiatric health. However, the potential role of DNA methylation in ADHD symptoms is currently unclear. In this study, we examined data from the Avon Longitudinal Study of Parents and Children (ALSPAC) – specifically the subsample forming the Accessible Resource for Integrated Epigenomics Studies (ARIES) – which includes (i) peripheral measures of DNA methylation (Illumina 450k) at birth (n=817, 49% male) and age 7 (n=892, 50% male) and (ii) trajectories of ADHD symptoms (7-15 yrs). We first employed a genome-wide analysis to test whether DNA methylation at birth associates with later ADHD trajectories; and then followed up at age 7 to investigate the stability of associations across early childhood. We found that DNA methylation at birth differentiated ADHD trajectories across multiple genomic locations, including probes annotated to SKI (involved in neural tube development), ZNF544 (previously implicated in ADHD), ST3GAL3 (linked to intellectual disability) and PEX2 (related to perixosomal processes). None of these probes maintained an association with ADHD trajectories at age 7. Findings lend novel insights into the epigenetic landscape of ADHD symptoms, highlighting the potential importance of DNA methylation variation in genes related to neurodevelopmental and peroxisomal processes, which play a key role in the maturation and stability of cortical circuits.

This study is the largest to date to characterize the contribution of exposure to bullying in childhood to mental health using a twin differences design and multi-informant, multiscale data. Stringent evidence of the direct detrimental contribution of exposure to bullying in childhood to mental health is provided. Findings also suggest that childhood exposure to bullying may partly be viewed as a symptom of preexisting vulnerabilities. Finally, the dissipation of effects over time for many outcomes highlights the potential for resilience in children who were bullied. In addition to programs that aim to reduce exposure to bullying, interventions may benefit from addressing preexisting vulnerabilities and focus on resilience.

Exposure to bullying victimization is associated with a wide-range of short and long-term adverse outcomes. However, the extent to which these associations reflect a causal influence of bullying victimization remains disputed. Here, we aimed to provide the most stringent evidence regarding the consequences of bullying victimization by meta-analyzing all relevant quasi-experimental (QE) studies. Multilevel random effects models and metaregression were employed to (a) estimate the pooled QE-adjusted effect size (Cohen d) for bullying victimization on outcomes and to (b) evaluate potential sources of heterogeneity. A total of 16 studies were included. We derived 101 QE-estimates from three different methods (twin design, fixed effects analysis, and propensity score matching) for three pools of outcomes (internalizing symptoms, externalizing symptoms, academic difficulties). QE-adjusted effects were small for internalizing symptoms (d adjusted ϭ 0.27, 95% CI [0.05, 0.49]), and smaller for externalizing symptoms (d adjusted ϭ 0.15, 95% CI [0.10, 0.21]) and academic difficulties (d adjusted ϭ 0.10, 95% CI [0.06, 0.13]). Accounting for a shared rater effect between the exposure and the outcome further reduced the effect for internalizing (d nonshared rater ϭ 0.14, 95% CI [0.05, 0.23]) and externalizing symptoms (d nonshared rater ϭ 0.06, 95% CI [0.01, 0.11]). Finally, the adverse effects declined in the long-term, most markedly for internalizing symptoms (d long-term ϭ 0.06, 95% CI [Ϫ0.01, 0.13]). Based on the most stringent evidence available to date, findings indicate that bullying victimization may causally impact children's wellbeing in the short-term, especially anxiety and depression levels. The reduction of adverse effects over time highlights the potential for resilience in individuals who have experienced bullying. Secondary preventive interventions in bullied children should therefore focus on resilience and address children's preexisting vulnerabilities. Public Significance StatementThis meta-analysis of quasi-experimental studies suggests that bullying victimization leads to poorer developmental outcome in the short-term, including higher internalizing and externalizing symptoms and reduced academic achievement. These adverse effects diminish in the long-term, highlighting the potential for resilience in individuals who experienced bullying. In addition to tackling bullying, interventions should therefore address the immediate adverse consequences of bullying victimization, while fostering resilience in victimized children.