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J. Felix

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Open access Aug 2026

Perinatal risk factors, DNA methylation and the development of ADHD symptoms: a high-dimensional mediation analysis

Background: Attention-deficit/hyperactivity disorder (ADHD) is associated with perinatal and genetic risk factors, including prenatal maternal smoking, pre-pregnancy BMI, gestational age, birth weight, and common genetic variants. These risk factors, as well as ADHD symptoms themselves, have previously been linked to cord blood DNA methylation (DNAm). We tested the hypothesis that cord blood DNAm mediates the effects of these risk factors on ADHD symptoms. Methods: Participants were drawn from two large European population-based cohorts: the Generation R Study and Avon Longitudinal Study of Parents and Children (n=3087). Cord blood DNAm was assessed using Illumina 450k and EPIC v1 arrays. ADHD symptoms were repeatedly measured with parent-based questionnaires between the ages 6 and 10 years. A high-dimensional mediational model based on DNAm principal components mediation analysis (PCMA) estimated the global mediation effect of all tested DNAm sites. Mediation via single principal components and individual DNAm sites was also evaluated using structural equation modeling and Divide-Aggregate Composite-null Test (DACT). Results: DNAm globally mediated the relationships of maternal smoking, low birth weight, and an ADHD polygenic score (PGS) with ADHD symptoms. Specifically, DNAm explained 62% of the total effect for maternal smoking, 56% for birth weight, and 35% for the ADHD-PGS. No association with individual principal components or single DNAm sites survived multiple testing correction. Evidence for mediation was absent for pre-pregnancy BMI and inconsistent for gestational age. Conclusions: In this first epigenome-wide mediation study of ADHD, we demonstrate a role of DNAm at birth in mediating the association of maternal smoking, birth weight and ADHD-related genetic variants with ADHD symptoms. However, lack of individual site-specific findings and the observational design limit causal biological interpretations. We therefore encourage further research of epigenetic pathways for these three risk factors.

A. Neumann, M. Suderman, J. Felix et al. · 0 citations
Open access Jul 2026

DNA methylation as proxy of genetic, prenatal and perinatal psychiatric risk factors

Background. Cord blood DNA methylation profile scores (MPSs) based on genetic and pre-/perinatal risk factors for neurodevelopmental conditions (NDCs) may capture downstream biological effects and help understand how combined exposure signals contribute to NDC risk. Methods. Using data from two longitudinal birth cohorts, Generation R (N-train = 1856, N-test = 476) and ALSPAC (N-validation= 832), we developed cord blood MPSs based on genetic and pre-/perinatal NDC risk factors. We assessed individual and combined predictive performance of risk factors and MPSs for eight childhood psychiatric outcomes (four broad, four specific), measured between ages 5 and 14 years. We also evaluated if the MPSs could be combined into a composite "transmission load" MPS. Results. We validated four novel MPSs: maternal age, birthweight, and genetic liability for ADHD and schizophrenia (r range = 0.08 to 0.29) and included two previously validated MPSs: maternal smoking and gestational age (r range = 0.42 to 0.63). Jointly modeling the six MPSs with their corresponding risk factors explained on average 3.3% of variance in outcomes, higher than that explained by risk factors (1.8%) or MPSs alone (1.6%), indicating complementary sources of risk. The "transmission load" MPS did not replicate due to heterogeneous contributions of the predictors across cohorts. Conclusions. The four novel MPSs based on genetic and pre-/perinatal risk factors can serve as valuable tools for future research. Integrating genetic and prenatal risk factors with DNA methylation at birth can provide insights into their individual and joint contributions to early psychiatric risk and may improve prediction.

Elena Isaevska, Rosa H. Mulder, Isabel K. Schuurmans et al. · 0 citations