BACKGROUND Genetic differences are robustly associated with educational outcomes, but how they become linked is poorly understood. A plausible hypothesis, yet to be thoroughly empirically tested, is that the school environment mediates the association. METHODS Using structural equation models, we tested whether the student-teacher relationship at age 5 (teacher-reported Student-Teacher Relationship Scale) mediated the association between children's education-linked genetic propensities (PGSedu) and mother-rated reading and math performance at ages 6-8. We performed these analyses in 63,032 children from the Norwegian Mother, Father and Child Cohort Study, a longitudinal, population-based, pregnancy cohort. RESULTS Higher PGSedu were significantly associated with lower student-teacher conflict (β = -0.08, p < .001) and positive teacher responses (β = 0.07, p = .001), but not student-teacher closeness (β = 0.01, p = .616). Associations between PGSedu and educational performance were significantly partially mediated via conflict (β = 0.01, p < .001) and positive teacher responses (β = 0.01, p = .019) but not closeness (β = 1 × 10-3, p = .619). CONCLUSIONS Student-teacher conflict and positive teacher responses may be mechanisms involved in the cascade of pathways linking children's genetics to their educational outcomes.

The underdiagnosis of Attention-Deficit/Hyperactivity Disorder (ADHD) in females, particularly those with the inattentive presentation, highlights a critical gap in clinical care. While DNA methylation may be tissue-specific, accessible peripheral measures such as cord blood can provide valuable insights into early-life risk and serve as potential biomarkers for detection. We aimed to discover sex-specific epigenetic markers in cord blood associated with childhood ADHD symptoms, which could illuminate early-life risk mechanisms and inform improved detection strategies. Method We conducted sex-stratified epigenome-wide association study (EWAS) of cord blood DNA methylation in relation to ADHD symptoms among child participants (n=2,417; 47% females) of the Norwegian Mother, Father, and Child study (MoBa). We tested for sex-interaction effects and analyzed inattention and hyperactivity/impulsivity symptoms separately. Results We identified 21 differentially methylated CpG positions (DMPs). The majority (n=13) were associated with inattention symptoms exclusively in females, and all exhibited significant sex-interaction effects (corrected p-value <0.05). There was no overlap between the DMPs, or differentially methylated regions (DMRs) identified in females and males, and the epigenetic signatures for inattention and hyperactivity/impulsivity were largely distinct. Several annotated genes (e.g., PNPO, KDM5B, and GABRP) have recognized roles in neurotransmission and neurodevelopment. Conclusion Our findings demonstrate that the peripheral epigenetic profile at birth associated with later ADHD is remarkably different between sexes. This highlights the value of sex-stratified analyses and suggests that peripheral epigenetic markers hold promise for the development of tools for early detection.

Research on mental health has traditionally separated the study of ill-being, including clinically defined mental and behavioural disorders and subthreshold problems, from the study of well-being, which encompasses factors such as life satisfaction and positive affect. Although previous reviews of studies primarily using self-report scales indicate that ill-being and well-being are distinct yet interconnected constructs, a deeper examination of their relationship is lacking. In this Perspective, we synthesize genetic, biological, developmental, psychosocial, societal, cultural and clinical research on ill-being and well-being. Our review reveals substantial genetic overlap and similar biological underpinnings for ill-being and well-being. By contrast, environmental factors and societal changes often exert divergent influences. We propose a differentiated multidisciplinary framework in which the shared and unique determinants, predictors, mechanisms and consequences of mental ill-being and well-being vary across levels of analysis, offering a more nuanced understanding of the interconnections. Tamnes et al. explore the complex relationship between ill-being—including mental and behavioural disorders—and mental well-being.

OBJECTIVE Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SCZ) are highly heritable and linked to disruptions in fetal neurodevelopment. Epigenetic processes, such as DNA methylation (DNAm), are considered a key pathway of interest. Yet, it is unclear whether: (i) genetic susceptibility to neurodevelopmental conditions associates with DNAm patterns already at birth; (ii) DNAm patterns are unique or shared across conditions, and (iii) neonatal DNAm patterns can be leveraged to enhance genetic prediction of neurodevelopmental outcomes. METHODS We conducted epigenome-wide meta-analyses of genetic susceptibility to ASD, ADHD, and schizophrenia (measured with polygenic scores [PGSs]) and cord blood DNAm in four European population-based cohorts (npooled=5,802; 50.2% female). We estimated DNAm pattern overlap between PGSs using heterogeneity statistics. Further, we built methylation profile scores for each PGS to test incremental variance explained over genetic data alone in 130 developmental outcomes from birth to 14 years. RESULTS In probe-level analyses, SCZ-PGS associated with neonatal DNAm at 246 loci (p<9x10-8), predominantly in the major histocompatibility complex, supporting an early-origins perspective on schizophrenia. Functional characterization confirmed strong genetic effects, blood-brain concordance and enrichment for immune-related pathways. 8 loci were identified for ASD-PGS (mapping to FDFT1 and MFHAS1), and none for ADHD-PGS. Differentially methylated regions were detected across PGSs (130-166 regions). Overall, DNAm signals were largely distinct between conditions. Incorporating neonatal DNAm data in genetic prediction models nominally increased explained variance for several cognitive and motor outcomes. CONCLUSIONS Genetic susceptibility for neurodevelopmental conditions, particularly schizophrenia, is detectable in cord blood DNAm in the general population.

Background It has long been hypothesized that increasing heritability with age of cognitive and educational performance is partly attributable to evocative gene–environment correlation. However, this hypothesis has not been widely tested. Methods We addressed this gap by examining whether children's education polygenic scores (PGSedu ) were associated with maternal self‐reported positive and literacy‐focused parenting when children were 5 years old, and if evoked parenting differences mediated genetic effects on children's educational outcomes (mother‐reported at 6–8 years of age), while controlling for parental PGSedu . We also investigated whether maternal reports of children's language at 5 years old were associated with parenting and mediated genetic effects on educational performance. These questions were addressed in a sample of 83,627 parent‐offspring trios from the Norwegian Mother, Father and Child Cohort Study, a longitudinal population‐based pregnancy cohort. Results Children's PGSedu were significantly associated with maternal literacy‐focused (β = .03, 95% CI [0.01, 0.05], p = .021) but not positive parenting (β = 0.01, 95% CI [−0.02, 0.05], p = .410), and literacy‐focused parenting significantly mediated the effects of children's PGSedu on their educational performance (β = 0.01, 95% CI [1 × 10−3, 0.01], p = .023). Children's language was associated with maternal parenting and mediated the effects of children's PGSedu on their educational performance (β = 0.01, 95% CI [3 × 10−3, 0.02], p = .002). Conclusions These findings support our hypotheses and suggest early language and parenting may be mechanisms implicated in the pathways from children's genetics to their educational outcomes.

Psychological stress during pregnancy is known to have a range of long-lasting negative consequences on the development and health of offspring. Here, we tested whether a measure of prenatal early-life stress was associated with a biomarker of physiological development at birth, namely epigenetic gestational age, using foetal cord-blood DNA-methylation data. Longitudinal cohorts from the Netherlands (Generation R Study [Generation R], n = 1,396), the UK (British Avon Longitudinal Study of Parents and Children [ALSPAC], n = 642), and Norway (Mother, Father and Child Cohort Study [MoBa], n1 = 1,212 and n2 = 678) provided data on prenatal maternal stress and genome-wide DNA methylation from cord blood and were meta-analysed (pooled n = 3,928). Measures of epigenetic age acceleration were calculated using three different gestational epigenetic clocks: “Bohlin”, “EPIC overlap” and “Knight”. Prenatal stress exposure, examined as an overall cumulative score, was not significantly associated with epigenetically-estimated gestational age acceleration or deceleration in any of the clocks, based on the results of the pooled meta-analysis or those of the individual cohorts. No significant associations were identified with specific domains of prenatal stress exposure, including negative life events, contextual (socio-economic) stressors, parental risks (e.g., maternal psychopathology) and interpersonal risks (e.g., family conflict). Further, no significant associations were identified when analyses were stratified by sex. Overall, we find little support that prenatal psychosocial stress is associated with variation in epigenetic age at birth within the general paediatric population.

Background. Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SCZ) are highly heritable and linked to disruptions in foetal (neuro)development. While epigenetic processes are considered an important underlying pathway between genetic susceptibility and neurodevelopmental conditions, it is unclear (i) whether genetic susceptibility to these conditions is associated with epigenetic patterns, specifically DNA methylation (DNAm), already at birth; (ii) to what extent DNAm patterns are unique or shared across conditions, and (iii) whether these neonatal DNAm patterns can be leveraged to enhance genetic prediction of (neuro)developmental outcomes. Methods. We conducted epigenome-wide meta-analyses of genetic susceptibility to ASD, ADHD, and schizophrenia, quantified using polygenic scores (PGSs) on cord blood DNAm, using four population-based cohorts (npooled=5,802), all North European. Heterogeneity statistics were used to estimate DNAm pattern overlap between PGSs. Subsequently, DNAm-based measures of PGSs were built in a target sample, and used as predictors to test incremental variance explained over PGS in 130 (neuro)developmental outcomes spanning birth to 14 years. Outcomes. Probe-level analyses showed SCZ-PGS associated with neonatal DNAm at 246 loci (p<9x10-8), predominantly in the major histocompatibility complex. Functional characterization of SCZ-PGS loci confirmed strong genetic effects, significant blood-brain concordance and enrichment for immune-related pathways. 8 loci were identified for ASD-PGS (mapping to FDFT1 and MFHAS1), and none for ADHD-PGS. Regional analyses indicated a large number of differentially methylated regions for all PGSs (SCZ-PGS: 157, ASD-PGS: 130, ADHD-PGS: 166). DNAm signals are largely unique for individual PGSs. Finally, a DNAm-based measure of genetic susceptibility at birth nominally increased explained variance for several child cognitive and motor outcomes above PGS, but not after multiple testing correction. Interpretation. Genetic susceptibility for neurodevelopmental conditions, particularly schizophrenia, is detectable in cord blood DNAm at birth in a population-based sample, with largely distinct DNAm patterns between PGSs. These findings support the early-origins perspective on schizophrenia. Funding. HorizonEurope; European Research Council Keywords. Population-based; Genetic susceptibility; DNA methylation; Epigenetics; Neurodevelopmental conditions; Generation R Study; PREDO; ALSPAC; MoBa

BACKGROUND Epidemiological studies suggest that the maternal diet quality during pregnancy may influence the risk of neurodevelopmental disorders in the offspring. Here we investigated the associations between maternal intake of dietary fiber and ADHD symptoms in early childhood. METHODS We used longitudinal data of up to 21,852 mother-father-child trios (49.2% females) from the Norwegian Mother, Father, and Child Cohort Study. The relationships between maternal fiber intake during pregnancy and offspring ADHD symptoms at ages three, five, and eight years were examined using: a) multivariate regression (overall levels of ADHD symptoms), b) latent class analysis (subclasses of ADHD symptoms by sex at each age), and c) latent growth curves (longitudinal change in offspring ADHD symptoms). Covariates were ADHD polygenic scores in child and parents, total energy intake and energy-adjusted sugar intake, parental ages at birth of the child, and socio-demographic factors. RESULTS a) Higher maternal prenatal fiber intake was associated with lower offspring ADHD symptom scores at all examined ages (βage3=-0.14(95%CI -0.18, -0.10); βage5=-0.14(-0.19, -0.09); βage8=-0.14(-0.20, -0.09)). b) Of the derived low/middle/high subclasses of ADHD symptoms, fiber was associated with lower risk of belonging to middle subclass for boys and girls, and to high subclass for girls only (middle: ORboys 0.91(0.86-0.97)/ORgirls 0.86 (0.81-0.91); high ORgirls 0.82 (0.72-0.94)). c) Maternal fiber intake and rate of change in child ADHD symptoms across ages were not associated. CONCLUSIONS A low prenatal maternal fiber intake may increase symptom levels of ADHD in childhood, independently of genetic predisposition to ADHD, unhealthy dietary exposures, and socio-demographic factors.

The goal of this prospective longitudinal study was to explore whether co-occurrent internalizing difficulties and aggression in early childhood convey increased risk for later mental health problems in middle childhood. Participants were mothers from the Norwegian Mother, Father and Child Cohort Study (MoBa), who provided assessments of child internalizing difficulties and aggression at ages 3 years (n = 54,644; 26,750 girls) and 5 years (n = 38,177; 18,794 girls), as measures of child depressive, anxiety, conduct-related, and oppositional defiant (OD) symptoms at age 8 years. Using latent profile analyses (LPA) of internalizing difficulties and aggression, four profiles were identified: low-symptom/normative; primarily internalizing; primarily aggressive; and co-occurrent. Among the other results, the co-occurrent group exhibited the highest levels of depressive, anxiety, and oppositional defiant symptoms at 8 years. Most children (78%) remained stable in their profile between ages 3 and 5 years. Among the transition patterns that emerged, transitions were observed both from the normative to a risk profile and vice versa. Children who remained stable within the co-occurrent profile or who transitioned from the co-occurrent profile to one of the other two risk profiles also exhibited more depressive, anxiety, and OD symptoms at 8 years of age, when compared with children who transitioned from the co-occurrent to the normative profile. The heterogeneity between early manifestation of internalizing difficulties and aggression, and specific type of later mental health symptoms not only supports a shared etiology between internalizing and externalizing difficulties but also points toward the need for person-centered monitoring in early childhood with further implications for early identification of difficulties and preventive measures.