Journal of Child Psychology and Psychiatry

BackgroundTemperament traits, which reflect early emerging individual differences in reactivity and regulation, are well-established correlates of psychopathology. However, studies have historically examined static temperament-psychopathology associations within limited age ranges. Research is required to understand the developmental dynamics of these associations. MethodsWe leveraged data from a longitudinal cohort (N = 767) with repeated measures in infancy and at ages 2 years, 3 years, 5 years, 7 years, and 11 years to examine predictive and concurrent associations between temperament traits (negative affectivity, surgency, effortful control, behavioral inhibition) and psychopathology (internalizing, externalizing) symptoms. We estimated time-varying associations using generalized additive mixed models to quantify variation in the significance and magnitude of associations from infancy through early adolescence. ResultsGreater negative affectivity consistently predicted higher internalizing and externalizing symptoms from infancy through 11 years. Surgency showed differential patterns, with higher surgency associated with lower internalizing symptoms but greater externalizing symptoms. Surgency from 2 years was associated with both internalizing and externalizing symptoms over proximal developmental intervals, whereas at 3 years, associations with externalizing extended distally through 11 years, while associations with internalizing remained proximal. Higher effortful control was associated with fewer internalizing and externalizing symptoms, with stronger effects for externalizing symptoms. Behavioral inhibition at 3 years was associated with internalizing symptoms ages 3 and 5 years. The significance and magnitude of associations between temperament domains and psychopathology symptoms varied based on developmental timing. ConclusionsTemperament traits show differential associations with psychopathology symptoms, depending on the specific temperament trait and psychopathology domain. Further, the significance and magnitude of associations vary based on developmental timing. These findings highlight the importance of considering differential traits, domains, and developmental timing when considering the potential role of temperament in psychopathology.

Common genetic variants make a significant contribution to neurodevelopmental characteristics such as cognitive abilities and ADHD symptoms. The relevance and structure of these associations amongst children with transdiagnostic difficulties in cognition, attention and learning has not been explored. Polygenic scores (PGS) derived from the largest genome-wide association study (GWAS) data at the time of this study on ADHD (38,691 individuals with ADHD and 186,843 controls) and Intelligence (269,867 individuals) were calculated for 524 children and young people (5-18 years old) referred to the Centre for Attention, Learning and Memory (CALM). PGS-trait associations were assessed via linear regression analyses, for a range of cognitive and behavioural dimensional measures, and factor scores from a hierarchical model of psychopathology. PGS associations were explored with and without co-varying for socio-economic status (SES). Within this sample, we found the expected positive associations between ADHD-PGS and ADHD primary symptoms, and between Intelligence-PGS and IQ. ADHD-PGS were also associated with broader externalising behaviours and intelligence scores, and these associations remained significant after removing ADHD-diagnosed participants, or after covarying with SES. Intelligence-PGS showed associations with verbal and non-verbal cognitive skills, but no significant associations with ADHD traits were detected. For the hierarchical model of psychopathology, ADHD-PGS, but not intelligence-PGS, showed associations with the general mental health factor, externalising factor, and social maladjustment factor, only when SES was not included as a covariate. In summary, PGS for neurodevelopmental traits may contribute to both general and specific cognitive and behavioural dimensions in a paediatric transdiagnostic sample. Future studies investigating PGS associations with neural correlates, as well as gene-by-environment interactions, will contribute to our understanding of developmental pathways and risk-resilience mechanisms in child mental health.

BackgroundExternalizing behavior refers to emotional and behavioral problems or disorders characterized by conducts directed outward at an individuals environment. Polygenic scores (PGSs) indexing the individual genetic susceptibility for this behavior still explain a small proportion of the phenotypic variance. To increase this phenotypic variance explained for externalizing behavior we used a multi-PGS approach combining PGSs for several risk factors, mental health conditions and related phenotypes. In addition, we assessed the potential moderating effect of socioeconomic status (SES). MethodsThe study included a total of 4,485 children and adolescents (mean age = 10.0 years; range = 5-18, 45% females) with behavioral and genetic data available. Externalizing behavior was assessed using the Child Behavior Checklist and PGSs were constructed using PRScs software. We tested two models and compared the proportion of variance that they explained: (i) a single-PGS model with the PGS for externalizing behavior (PGSexternalizing) and (ii) a multi-PGS model combining the PGSexternalizing with other PGSs for risk factors grouped in six categories: environment, mental-health, cognition, personality, health-risk behaviors and non-mental diseases. ResultsThe multi-PGS models for the categories of environment, mental-health, cognition and health-risk behaviors improved the variance explained of externalizing behavior in 20.9%, 37.6%, 35% and 34.2%, respectively, over the single model only including PGSexternalizing. Furthermore, we observed significant interactions between SES and the multi-PGS models of environment, mental-health, cognition and health-risk behaviors (P-interaction < 0.05), indicating that in individuals with lower SES, the influence of these four multi-PGSs on externalizing behavior is stronger. ConclusionThis study provides new insights into the genetic architecture of externalizing behavior in a population-based cohort of children and adolescents and further supports the utility of incorporating multiple PGSs into predictive models to improve accuracy, increase the proportion of variance explained, and maximize the predictive utility of PGSs. Additionally, by assessing GxE, we contribute to understanding the complex relationship between SES and mental health outcomes, highlighting its impact on youth.

BackgroundComorbidity and heterogeneity in psychiatric disorders may stem from a general psychopathology (p) factor influenced by both genetic and environmental factors. Although the relative contributions of these influences on psychopathology are established, the longitudinal associations between p-factor and specific environmental exposures across development are not well understood. Using a longitudinal genetically informative design, this study investigates the association between the home environment and p-factor across childhood. MethodsData were obtained from the Twins Early Development Study (TEDS). Cross-lagged panel analyses were conducted separately to ascertain the direction of associations between parent-rated p, self-rated p, and self-rated home environment (chaos at home and parental discipline) at ages 9, 12, and 16 (N=6,213). Biometric autoregressive cross-lagged twin models were used to assess the aetiology of these associations, and MZ differences analyses were used to control for familial effects. ResultsBoth latent factors were stable over time, although twin-rated p-factor (r = 0.44-0.40) was more variable than parent-rated p-factor (r = 0.72-0.63). Home environment was more variable than p-factor uniformly. Small, significant bi-directional associations were found between p-factor and home environment, with stronger cross-lagged paths from p-factor to home environment than vice versa. These longitudinal associations persisted over time, though attenuated for parent-rated p-factor. Genetic analyses revealed that bi-directional cross-lagged paths were largely explained by shared environmental factors, with a smaller proportion explained by genetic factors. This pattern of results was confirmed in MZ differences analyses. ConclusionsOur findings suggest a dynamic and bidirectional relationship between p-factor and the home environment across development, predominantly influenced by shared environmental factors. Changes in one can influence the other, highlighting the complexity of psychopathologys environmental influences. This underscores the need for further investigation into gene-environment interplay to inform approaches to psychopathology prevention and intervention. Key points and relevanceO_LIThe relationship between p-factor and the home environment is dynamic and bidirectional, indicating that changes in one can influence the other across different developmental stages. However, the effect sizes of these relationships were modest. C_LIO_LIShared environmental factors played a major role in driving cross-lagged associations between p-factor and the home environment, with some genetic contribution, suggesting that the family environment can significantly shape this relationship. C_LIO_LIThese findings necessitate deeper investigations into gene-environment interplay in shaping psychopathology. A better understanding of these dynamics could inform effective prevention and intervention strategies for developmental psychopathology. C_LI

Behaviors and disorders characterized by difficulties with self-regulation, such as problematic substance use, antisocial behavior, and symptoms of attention-deficit/hyperactivity disorder (ADHD), incur high costs for individuals, families, and communities. These externalizing behaviors often appear early in the life course and can have far-reaching consequences. Researchers have long been interested in direct measurements of genetic risk for externalizing behaviors, which can be incorporated alongside other known risk factors to improve efforts at early identification and intervention. In a preregistered analysis drawing on data from the Environmental Risk (E-Risk) Longitudinal Twin Study (N=862 twins) and the Millennium Cohort Study (MCS; N=2,824 parent-child trios), two longitudinal cohorts from the UK, we leveraged molecular genetic data and within-family designs to test for genetic effects on externalizing behavior that are unbiased by the common sources of environmental confounding. Results are consistent with the conclusion that an externalizing polygenic index (PGI) captures causal effects of genetic variants on externalizing problems in children and adolescents, with an effect size that is comparable to those observed for other established risk factors in the research literature on externalizing behavior. Additionally, we find that polygenic associations vary across development (peaking from age 5-10 years), that parental genetics (assortment and parent-specific effects) and family-level covariates affect prediction little, and that sex differences in polygenic prediction are present but only detectable using within-family comparisons. Based on these findings, we believe that the PGI for externalizing behavior is a promising means for studying the development of disruptive behaviors across child development. Significance StatementExternalizing behaviors/disorders are important but difficult to predict and address. Twin models have suggested that externalizing behaviors are heritable ([~]80%), but it has been difficult to measure genetic risk factors directly. Here, we go beyond heritability studies by quantifying genetic liability for externalizing behaviors using a polygenic index (PGI) and employing within-family comparisons to remove sources of environmental confounding typical of such polygenic predictors. In two longitudinal cohorts, we find that the PGI is associated with variation in externalizing behaviors within families, and the effect size is comparable to established risk factors for externalizing behaviors. Our results suggest that genetic variants associated with externalizing behaviors, unlike many other social-science phenotypes, primarily operate through direct genetic pathways.

BackgroundScreen use is pervasive in childhood and adolescence, yet its role in antisocial behaviour (ASB) remains uncertain. While cross-sectional studies consistently link higher screen use to elevated ASB, longitudinal evidence is mixed, and few studies have controlled adequately for prior behaviour and genetic liability. Thus, it remains unclear whether these associations reflect prospective influences of screen exposure, or underlying vulnerabilities shared with ASB. We investigated whether screen use is a modifiable risk factor or a marker of underlying vulnerability. MethodsWe analysed data from up to 41,562 children in the Norwegian Mother, Father, and Child Cohort Study (MoBa). ASB traits and ICD-10-based conduct disorder (CD) diagnoses were assessed at ages 5, 8 and 14 years, together with screen use (total exposure and modality). Cross-sectional logistic regression models examined associations between screen use and ASB traits/CD at each age, adjusting for sex and parental education. Polygenic risk scores for ASB (PRSASB) were used to assess genetic susceptibility and gene-environment interplay. Lagged logistic models tested whether screen use predicted later ASB, adjusting for prior ASB. Linear mixed-effects models examined developmental patterns across age. ResultsHigher screen use was positively associated with ASB traits and CD across all ages, with dose-response patterns across screen-use modalities. Social media showed the strongest modality-specific association at adolescence. In lagged models, screen use did not predict later ASB after adjustment for prior ASB. Longitudinal models showed significant but attenuating associations across development. PRSASB was independently and additively associated with ASB outcomes but did not interact with screen use. ConclusionsWe found that higher screen use was consistently associated with antisocial outcomes across childhood and adolescence. However, the absence of prospective associations after accounting for prior behaviour, together with independent genetic contributions, suggests that screen use may be better understood as a marker of underlying vulnerability rather than an independent driver of antisocial development.

BackgroundHigh cognitive ability is an almost universally positive prognostic indicator in the context of neurodevelopmental, neuropsychiatric, and neurodegenerative conditions. However, "twice-exceptional" individuals, those who demonstrate exceptionally high cognitive ability (gifted) and exhibit profound behavioral and mental health challenges, are a striking exception to this rule. MethodsWe digitized the clinical records of N=1,074 clients from a US-based specialty clinic serving gifted students. This included a broad array of diagnostic, cognitive, achievement, and behavioral data, including self, teacher, and parent reported items. We conducted both hypothesis-driven and unsupervised learning analyses to 1) identify characteristics whose association with full-scale IQ (FSIQ) was dependent on autism diagnosis and 2) identify cognitive archetypes associated with autism diagnosis and related behaviors. We tested the generalization of our findings using data from the SPARK (N=17,634) and ABCD studies (N=10,602). ResultsAutistic individuals with IQ >= 120 were nearly 15 times more likely to enter adulthood undiagnosed compared to lower-IQ (IQ < 70) counterparts. Self-reported sense of inadequacy was most strongly associated with increasing FSIQ specifically among autistic clients (beta=0.3, 95% CI:[0.15,0.45], p=7.1x10-5). Similarly, self, parent, and teacher reports of anxiety increased with FSIQ (all p<0.05) in autistic individuals, in striking opposition to the ameliorating effect of FSIQ seen in non-autistic individuals. We uncovered a pattern of decreased processing speed (PS) coupled with very high verbal comprehension (VC), a PS/VC discrepancy, that was associated with autism, inattention, and internalizing problems. Similar cognitive-behavioral links were also observed in the ABCD study. Finally, we found a significant association between the PS/VC discrepancy and polygenic risk for autism in the ABCD sample (t=2.9, p=0.004). ConclusionsOur results suggest that autistic individuals with exceptional ability are underserved and suffer disproportionately from high anxiety and low self-worth. In addition, elevated IQ with a significant PS/VC discrepancy appears to be a clinically and genetically meaningful biotype linked to autism.

BackgroundNeurodevelopmental and mental health disorders in childhood constitute an emerging global concern, with adverse sequelae which span childrens physical, psychological and social well-being. The aetiology of these disorders is likely complex, multifactorial and polygenic. Polygenic risk scores (PRS), an estimate of an individuals genetic liability toward a disorder, have been increasingly used in psychiatric research to explore genetic associations with disorders of interest. However, limited work delineates polygenic associations with development and mental health in childhood populations. We aimed to systematically review existing literature on associations between genetic risk (as measured by PRS) and neurodevelopmental and mental health outcomes in childhood and adolescence. MethodsFollowing the recommended Preferred Reporting Items for Meta-Analyses (PRISMA) guidelines, databases were searched using key search terms. The search commenced in March 2021 and concluded in June 2021. The studies eligible for inclusion were full-text articles investigating polygenic risk associations with neurodevelopmental and/or mental health outcomes in childhood or adolescence. ResultsFourteen studies were eligible for inclusion in this systematic review. The association between higher PRS for attention-deficit/hyperactivity disorder (ADHD) and adverse developmental/mental health outcomes in childhood and adolescence was reported by five studies. Additionally, associations between PRS for bipolar disorder or major depressive disorder and adverse outcomes of interest were also described by two studies; and two studies highlighted associations between schizophrenia PRS and mental health disorders in childhood. The remaining studies highlighted shared polygenic contributions between and within NDDs and mental health disorders in children. ConclusionThe findings of this systematic review suggest that PRS for neurodevelopmental and mental health disorders may associate with adverse neurodevelopmental and mental health outcomes from early childhood to adolescence. In addition, these associations seemed not to be phenotype-specific, suggesting potential shared genetic variation across the phenotypes of interest.

Objective: ADHD has been associated with obesity indicators, including BMI, across the lifespan. A possible mechanism linking ADHD and BMI is binge eating. Previous research has found associations between ADHD, binge eating and BMI. However, the role of genetic and environmental influences on these associations remains unclear. Method: We utilized data from the Twins Early Development Study (TEDS), comprising 3,675 monozygotic and 7,063 dizygotic twin pairs. ADHD symptoms in childhood and adolescence were assessed using parent-reported questionnaires. Adult ADHD symptoms were measured using both self-report and parent-report questionnaires. Phenotypic mediation models examined whether binge eating mediated the association between ADHD and BMI, without controlling for genetic confounding. Subsequently, the etiological architecture underlying the associations among the three traits across childhood, adolescence, and adulthood were investigated by incorporating genetic and environmental influences into the models. Results: Binge eating significantly mediated the association between ADHD symptoms and BMI in both adolescence and adulthood. However, these mediation effects were no longer present once genetic and environmental influences were incorporated into the models. The best-fitting model in childhood, adolescence and adulthood was Cholesky decomposition models, where covariance between traits was explained by shared aetiology. Conclusions: This twin study reveals shared liability across ADHD, binge eating, and BMI. The mediating role of binge eating in the relationship between ADHD symptoms and BMI was largely confounded by shared genetic influences. Intervention strategies could focus more on common underlying behavioural and self-regulatory mechanisms across these traits, as well as placing more emphasis on symptom patterns within families.

IMPORTANCEExecutive function (EF) is crucial for adolescent development and mental health. However, population-level benchmarks of EF growth and their relevance to psychiatric symptoms remain unclear, especially for non-Western populations. OBJECTIVETo establish normative developmental charts of EF across adolescence and examine how deviations from these norms relate to mental health symptoms in an age-specific manner. DESIGNPrimary data were drawn from the baseline data of the ongoing Adolescent Health Enhancing Long-term Plan (A-HELP) study (2022-2027), with replication from three waves of longitudinal data (2016-2022) from the Adolescent Brain Cognitive Development (ABCD) study. SETTINGPopulation-based studies conducted in China (A-HELP). PARTICIPANTSThe A-HELP sample included 33,622 Chinese adolescents (11.00-18.00 years; 16,558 males) who completed EF tasks and mental health assessments. Normative developmental charts were constructed using generalized additive models for location, scale, and shape, from which individual EF deviation scores were derived. Associations with mental health were examined using generalized additive models, including age-varying interaction analyses. Replication were performed in 11,549 U.S. adolescents (8.92-15.75 years; 6,010 males) from the ABCD study. MAIN OUTCOMES AND MEASURESThree EF tasks were assessed: Go/No-Go (inhibitory control), 1-back and 2-back (working memory). Mental health symptoms were measured using the Strengths and Difficulties Questionnaire, including emotional symptoms, conduct problems, peer problems, hyperactivity/inattention, and prosocial behavior. RESULTSAdolescents completed Go/No-Go (N=17,021), 1-back (N=15,945), and 2-back (N=10,167) tasks. All tasks showed significant age-related improvement and decreasing inter-individual variability. Higher EF deviation scores, which reflect better performance, were associated with fewer peer and conduct problems, lower hyperactivity/inattention, and greater prosocial behavior. Age-resolved analyses revealed that these associations varied across development, with stronger effect sizes observed in early adolescence that declined by late adolescence. Findings were replicated in 22,831 Flanker task observations from the ABCD study, showing consistent developmental patterns and EF-mental health associations. CONCLUSIONS AND RELEVANCEThis study establishes normative developmental charts of EF in adolescence and highlights that deviations from these norms are linked to psychiatric symptoms, especially in early adolescence. These findings provide a developmental framework for identifying youth at risk of mental health difficulties, offering culturally generalizable benchmarks for early screening and intervention.

Disruptive behavior disorders among youth are a pressing public-health concern and a key pathway of intergenerational risk. In the 8-year longitudinal Geneva Early Childhood Stress Study, we tested whether maternal psychological, behavioral, and neurobiological factors assessed in toddlerhood predicted peri-pubertal disruptive behaviors. Mother-child dyads (n = 28; child age at Phase 1 = 12-44 months; Phase 3 = 9-15 years) completed clinical interviews; mothers underwent fMRI while viewing emotion-related (prosocial/romantic and threatening vs neutral) and threat-related (threatening vs prosocial/romantic) adult interactions; maternal sensitivity (MS) was coded from filmed play; child disruptive symptoms were assessed with the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) at follow-up. Ten a priori neural clusters were reduced via principal components analysis, yielding a theory-consistent Neural-Threat component and a Neural-Preoccupation component reflecting precuneus activity. Using exploratory forward stepwise regression adjusted for child age, sex, and socioeconomic status, Neural-Threat and MS each uniquely predicted fewer disruptive behaviors (protective), whereas Neural-Preoccupation predicted more symptoms (risk). A planned moderation test showed that MS buffered the Neural-Threat-behavior association, with stronger protection at higher sensitivity. Maternal posttraumatic stress severity in early childhood showed no direct association with later disruptive behaviors. These findings suggest that stress-responsive maternal brain function relates to childrens disruptive outcomes and that sensitive caregiving may potentiate protective neural processes. Results are preliminary and warrant replication in larger, more representative samples, but they highlight neurobehavioral targets for early, trauma-informed prevention, i.e., enhancing maternal sensitivity and supporting adaptive threat monitoring in mothers.

IntroductionEarly life adversity (ELA) is associated with increased internalizing and externalizing behavior in high-income cohorts. It is unclear to what extent these associations generalize to low- and middle-income countries (LMICs). We examined the association between ELA and internalizing and externalizing behaviors in children across three LMIC cohorts. MethodsData from three LMIC cohorts, the Brazilian High-Risk Cohort (BHRC; n = 1111), Sustainable Programme Incorporating Nutrition and Games (SPRING; n = 601), and Drakenstein Child Health Study (DCHS; n = 708) were pooled. Children (7-10 years) were assessed using the Strengths and Difficulties Questionnaire (SDQ). ELA (first 24 months) was assessed using a cumulative index. Ordinary Least Squares linear regression models were run to examine the associations of adversity with internalizing and externalizing behaviors while adjusting for child age, sex, and cohort, and to test interactions with child age and cohort. ResultsMeasurement invariance did not hold across cohorts, necessitating within-cohort analyses. 2420 children (53.9% boys) were included in analyses. ELA was associated with higher SDQ total scores (B = 1.97, 95% CI: 1.16, 2.78, p < .001), internalizing (B = 0.84, 95% CI: 0.41, 1.27, p < .001), and externalizing behaviors (B = 1.13, 95% CI: 0.62, 1.64, p < .001) in the full sample. Cohort-specific associations were strongest in the BHRC, with attenuated effects in SPRING and DCHS. Girls and older children exhibited fewer behavior problems. Interaction analyses indicated that the associations of adversity with behavior were stronger at younger ages and varied across cohorts. ConclusionIn cohorts from the Global South, while there is an association between early life adversity and psychopathology, there are also important context-dependent differences across cohorts.

BackgroundAdolescent mental health issues were surging during COVID-19 pandemic. Yet it is unclear whether the pandemic amplified pre-existing vulnerabilities for psychiatric disorders. MethodsUsing the longitudinal data from Adolescent Brain Cognitive Development (ABCD) Study(C) (n = 7,560, 2[~]3 waves of assessments before pandemic and 2[~]3 waves after first nation-wide pandemic lock-down), we evaluated associations of the pandemic, genetic liabilities to psychiatric disorders, and their interactions with 20 different measures of psychopathology. Genomic common factor models aggregated genomic effects across eight psychiatric disorders, summarizing into four latent factors. Analyses were stratified by genetic ancestry and sex. ResultsIn European-like ancestry adolescents, each 1 standard deviation increase in Neurodevelopmental (ND) or Internalizing (INT) PRS significantly associated with increment in most psychopathologies by 3% to 19%. After controlling for individuals PRS, pandemic periods were significantly associated with accelerated rates in parent-reported Child Behavior Checklist (CBCL) withdrawn depressed and rule-breaking syndrome scores, CBCL DSM-oriented conduct, somatic, and attention deficit/hyperactivity problems, and all corresponding youth-reported Brief Problem Monitor (BPM-Y) scores. In sex stratified analysis, CBCL DSM-oriented affective problem scores significantly worsened in early pandemic among females (21% increase; 95%CI 13%-29%; P=2.6x10{square}{square}) but not males. Females have stronger associations between INT PRS and rate of increment on CBCL DSM-oriented affective problem scores (15%; 95%CI 10%-21%; P=6.4x10{square}{superscript 1}{square}), comparing to males (10%; 95%CI 6%-15%; P=4.2x10{square}{square}). The multiplicative interactions between PRS and pandemic periods were at-most trending, showing positive interactions between ND PRS and early pandemic among females for CBCL conduct (15%; 95%CI 7%-23%; P=5.17x10{square}{square}) and aggressive behavior scores (9%; 95%CI 4%-14%; P=5.09x10{square}{square}). ConclusionA wide range of adolescent mental health symptoms intensified during the pandemic period. Both genetic vulnerabilities and pandemic-related factors are associated with increased psychiatric symptoms. The genetic liability and the pandemic periods were associated with mental health issues independently, meaning genetically at-risk individuals saw a higher relative increase in mental problems during the pandemic. Females exhibited higher levels of mental health symptoms and more sustained increases across the duration of the pandemic compared to males. Youth with genetic vulnerability to neurodevelopmental phenotypes required special attention due to heightened mental health risks during stressors like COVID-19.

A combination of genetic and environmental factors working in interplay is thought to underlie differences in symptoms of psychopathology between adolescents. Yet, studies that have investigated gene-environment interaction in isolated aspects of developmental psychopathology lack robust effects, highlighting the need for a more comprehensive approach. We adopted a multivariable framework to investigate gene-environment interaction in internalising and externalising symptoms of psychopathology in a sample of 3,337 16-year-olds from the Twins Early Development Study. We used penalised regression models to examine the main effects of genetic factors (G), indexed combining 13 polygenic scores for psychopathology, and environmental factors (E), measured by combining multiple environmental exposures during childhood and adolescence, on symptoms of psychopathology. We also examined their additive effects (G+E) and their interaction (GxE). Polygenic scores accounted for, on average, 2.7% of the variance in symptoms of psychopathology, with stronger predictions for externalising symptoms, while environmental measures alone accounted for an average of 7.1% of the variance. G+E accounted for an average of 9.1% of differences between adolescents in symptoms of psychopathology. We observed small GxE effects for internalising symptoms, accounting for an average of 1.1% of the variance. Children with a higher genetic risk showed higher levels of internalising symptoms, especially when exposed to more chaos at home and harsher parenting. Our findings indicate that genetic and environmental influences contribute additively, underscoring the importance of jointly considering both factors to enhance our understanding of youth psychopathology. At the same time, our results highlight the persistent challenges involved in identifying robust GxE effects.

Maternal internalizing (anxiety and depressive) symptoms are a robust risk factor for the development of internalizing symptoms in offspring, yet the neurobiological mechanisms that influence this association remain relatively unexplored. The aperiodic slope of the EEG power spectrum (i.e., aperiodic exponent) is hypothesized to index the cortical excitatory-inhibitory balance and may serve as an early neurophysiological marker of mental health risk. In a prospective longitudinal cohort (N = 322 mother-child dyads), we examined associations among maternal anxiety and depressive symptoms in infancy and at age 5 years, child EEG aperiodic slope at age 3 years, and child internalizing symptoms at age 5 years. We investigated whether the aperiodic slope at 3 years (a) mediated associations between maternal internalizing symptoms in infancy and child internalizing symptoms at age 5 years and/or (b) moderated associations between maternal internalizing symptoms and child internalizing symptoms at age 5 years. There were no significant mediation effects. The aperiodic slope moderated the association between maternal anxiety symptoms and child internalizing symptoms: A steeper slope was associated with a stronger association between maternal and child symptoms. Findings suggest that the EEG aperiodic slope may represent a moderator of intergenerational risk for internalizing symptoms in early childhood.

BackgroundNumerous studies have reported associations between environmental exposures and ADHD. However, whether environmental effects are causal or due to confounding with other familial factors, such as genetic risk, is still unclear. A more complete understanding of which environmental risk factors are causal remains crucial. MethodsUsing one population (ABCD cohort, N=11646) and one case-control cohort (Oregon ADHD-1000, N=744), we conducted both full-cohort and sibling-control analyses (770 and 152 families in ABCD and Oregon ADHD-1000, respectively) to assess the association of family environment and perinatal risk factors with ADHD symptoms. Within-family effects were compared to effects estimated in the full cohorts. We also assessed the impact of gene-environment correlation using child polygenic risk scores and measures of maternal mental health. ResultsFor both cohorts, full-cohort analyses yielded significant associations between child ADHD symptoms and family conflict, perinatal health factors, and breastfeeding duration (p-values <0.001). These associations were non-significant after accounting for family-level confounds (e.g., genetic risk and shared family environment) in exposure-discordant sibling-control analyses. In the full cohorts, effect sizes were substantially reduced (an average 43.7% decrease in effect size across all exposures tested in the ABCD cohort; average 47.6% decrease in Oregon ADHD-1000) after adjusting for child ADHD polygenic risk and measures related to maternal mental health. ConclusionsThe full-cohort associations between child ADHD symptoms and environmental risks confirm associations from prior research, but current findings do not indicate direct causal effects. Instead, much or all of the observed risk appears due to confounding with family-level factors, likely including genetic factors. Our results underscore the importance of accounting for familial risk factors that may confound relationships between behavioral traits and environmental exposures by using multiple study designs. Key PointsO_LINumerous environmental risk factors are associated with ADHD, but whether these are important casual associations is insufficiently studied. C_LIO_LISignificant associations between child ADHD symptoms and features of the family environment and perinatal health were replicated in two independent cohorts, confirming prior work. C_LIO_LISibling-control analyses provided no consistent evidence of causal relationships for any of the risk factors studied. Furthermore, accounting for factors related to genetic risk and parental mental health substantially reduced the observed effect sizes in full-cohort analyses. C_LIO_LIFindings are consistent with previous studies on the effects of breastfeeding duration and some substance exposures (e.g., smoking during pregnancy), suggesting associations are largely due to confounding with unmeasured familial factors. C_LIO_LIFurther study is warranted regarding potential sex differences in exposure associations with ADHD symptoms, as well as more complex causal pathways (e.g., gene-environment or environment-environment interaction). C_LI

BackgroundA range of rare chromosomal micro-deletions or -duplications (Copy Number Variants - CNVs) are associated with high risk of neurodevelopmental and mental health conditions (ND-CNVs). There is great individual variability in outcomes, but we lack insights into the contributing social factors, including family functioning. MethodsCaregivers of 598 children and young people (CYP) with a range of 16 ND-CNVs and 222 siblings without ND-CNVs (controls) completed questionnaires on overall family climate (cohesion and conflict) as well as caregiver-CYP relationship warmth and hostility and took part in a research diagnostic interview about CYPs psychiatric symptoms. CYPs intelligence quotient (IQ) was also measured. ResultsComparisons with published data from neurotypical families indicated that families affected by ND-CNVs are characterised by higher family cohesion and conflict as well as lower caregiver-CYP warmth and hostility. Symptoms of oppositional defiant disorder reduced more steeply in CYP with ND-CNVs compared to controls with increasing family cohesion (interaction effect: {beta} = -0.14, p = 4.65 x 10-{superscript 2}). In contrast, they rose more steeply with increasing family conflict (interaction effect: {beta} = 0.18, p = 1.05 x 10-{superscript 2}). Furthermore, symptoms of mood disorder increased more steeply with increased caregiver-CYP hostility in CYP with ND-CNVs (interaction effect: {beta} = 0.15, p = 4.55 x 10-{superscript 2}). ConclusionsRaising a CYP with a rare genetic condition is challenging. Timely access to interventions that support caregivers in fostering a positive family environment may reduce behavioural difficulties in CYP, with subsequent benefits for family functioning.

BackgroundThe genetic and environmental aetiology of autistic and Attention Deficit Hyperactivity Disorder (ADHD) traits is known to vary spatially, but does this translate into variation in the association of specific common genetic variants? MethodsWe mapped associations between polygenic scores for autism and ADHD and their respective traits in the Avon Longitudinal Study of Parents and Children (N=4,255 to 6,165) across the area surrounding Bristol, UK, and compared them to maps of environments associated with the prevalence of autism and ADHD. ResultsOur maps suggest genetic associations vary spatially, with consistent patterns for autistic traits across polygenic scores constructed at different p-value thresholds. Patterns for ADHD traits were more variable across thresholds. We found that the spatial distributions often correlated with known environmental influences. ConclusionsThese findings shed light on the factors that contribute to the complex interplay between the environment and genetic influences in autism and ADHD traits. Key pointsO_LIThe prevalence of autism and ADHD vary spatially. C_LIO_LIOur study highlights that genetic influences based on PGS also vary spatially. C_LIO_LIThis spatial variation correlates with spatial variation in environmental characteristics as well, which would be interesting to examine further. C_LIO_LIOur findings have implications for future research in this area examining the factors that contribute to the complex interplay between the environment and genetic influences on autistic and ADHD traits. C_LI

Research has demonstrated the transdiagnostic importance of irritability in psychopathology pathways but the contribution of developmentally-unfolding patterns has only recently been explored. To address this question, irritability patterns of 110 youth from a large and diverse early childhood cohort were assessed at preschool age and at school age ([~]2.5 years later) with a dimensional irritability scale designed to capture the normal:abnormal spectrum. Participants then returned at Pre-adolescence ([~]6 years later) for an assessment with a structured clinical interview (internalizing/externalizing symptoms) and a magnetic resonance imaging scan. When only preschool age irritability was considered, this was a transdiagnostic predictor of internalizing and externalizing symptoms. However, a model including both preschool and school age irritability provided a more nuanced picture. A high preschool and decreasing school age profile of irritability predicted elevated pre-adolescence internalizing symptoms, potentially reflecting emerging coping/internalizing behavior in pre-adolescence. In contrast, a stable irritability profile across these timepoints predicted increased pre-adolescence externalizing symptoms. Further, preschool irritability (a period of rapid growth) did not predict pre-adolescent gray matter volume abnormality, an indicator of transdiagnostic clinical risk. However, irritability at school age (when gray matter volume growth is largely finished) demonstrated an interactive effect among regions; increased school age irritability predicted reduced volume in pre-adolescence emotional regions (e.g., amygdala, medial orbitofrontal cortex) and increased volume in other regions (e.g., cerebellum). Expanding the impact of RDoCs approach yielding transdiagnostic phenotypes and multiple units of analysis, a developmentally informed approach provides critical new insights into the complex unfolding of mechanisms underlying emerging psychopathology.

ObjectiveWe examined whether common and specific genetic liabilities for internalized (INT) and externalized (EXT) traits predict corresponding disorders in Mexican youth, and whether adversity moderates these associations. MethodsParticipants were 1,130 Mexican adolescents (ages 12-17; 54.9% female). Psychiatric diagnoses and adversities were assessed using the World Mental Health Composite International Diagnostic Interview for Adolescents. Genome-wide association summary statistics for 12 INT and EXT traits were analyzed using genomic structural equation modeling (SEM) to derive polygenic scores (PGS) from latent genetic factors. Associations were tested using multinomial logistic regression. ResultsThe best-fitting genomic SEM bifactor model included one shared internalizing-externalizing factor (INT-EXT-F) and specific factors for internalizing (INT-SF) and externalizing (EXT-SF). Higher INT-EXT-F PGS predicted EXT-only (OR=1.39, 95%CI= 1.16-1.67) and comorbid disorders (OR=1.42, 95% CI= 1.16-1.75). Parental loss moderated associations between EXT-SF PGS and INT-only (OR=1.76, 95% CI= 1.17-2.64) and comorbid disorders (OR=1.79, 95% CI= 1.14-2.81). Cumulative adversity further increased risk, with higher EXT-SF PGS predicting INT (OR= 1.76; 95% CI= 1.17-2.64), EXT (OR= 1.79; 95% CI= (1.14-2.81), and comorbid outcomes (OR= 1.24; 95% CI= 1.04-1.48), and higher INT-EXT-F PGS predicting INT-only disorders (OR= 1.27; 95% CI = 1.07-1.50). ConclusionThese findings emphasize the value of combining genetic and environmental approaches in mental health studies among Mexican youth, broadening the reach and relevance of psychiatric genomic research beyond European populations.