RESUMEN
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 (n pooled=5,802), all North European. Heterogeneity statistics were used to estimate overlap in DNAm patterns 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: In probe-level analyses, SCZ-PGS associated with neonatal DNAm at 246 loci (p<9×10-8), predominantly in the major histocompatibility complex. Functional characterization of these DNAm 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 showed little overlap between PGSs. We found suggestive evidence that incorporating DNAm-based measures of genetic susceptibility at birth increases explained variance for several child cognitive and motor outcomes over and above PGS. 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 an early-origins perspective on schizophrenia. Funding: HorizonEurope; European Research Council.
RESUMEN
AIM: To determine the association between intrauterine exposure to timing and sources of caffeine and inattention/overactivity, suggesting ADHD in the child. METHOD: This study used prospectively collected data from the large population-based study, The Norwegian Mother and Child Cohort Study (MoBa). Participants were 25 343 mothers and their 18-month-old children. Mothers reported on consumption of a number of caffeine sources at the 17th week and 30th week of gestation, as well as child inattention/overactivity at 18 months. Data were analysed using univariate analyses of covariance (ancova). RESULTS: Once we controlled for confounders, there was a small effect of caffeine intake at 17th week of gestation on inattention/overactivity combined, and both 17th and 30th week of gestation on overactivity, when investigated separately from inattention. Surprisingly, the caffeine effect was only found for soft drinks, not tea or coffee. CONCLUSION: Intrauterine exposure to soft drinks rather than coffee, the traditional focus, is associated with maternal reports of overactive behaviour in children aged 18 months.