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