Background. DNA methylation patterns in cord blood are robustly associated with birthweight in the general population. However, it remains unknown whether these associations extend to clinically relevant populations, such as preterm neonates or those born small for gestational age, and whether they directly reflect birthweight or are driven indirectly by genetic, familial, maternal, and obstetric factors. Methods. We calculated a birthweight methylation profile score (MPSBW) using weights of 835 CpGs previously associated with birthweight in the general population and evaluated its association with birthweight in 67 monochorionic (MC) twin pairs including 134 neonates (97% born preterm) from the Twinlife study. MC twin pairs are identical twins sharing a single placenta, often unequally, which can result in unequal resource distribution and differential fetal growth. Results. We examined the association between within-pair differences in birthweight and MPSBW, thereby estimating the association independent of factors shared equally by co-twins. A 500-gram increase in birthweight was associated with a 0.256 SD increase in MPSBW (p<0.005) in this population of preterm neonates. Adjustment for polygenic score for birthweight (PGSBW) confirmed that the observed epigenetic associations were not driven by common genetic variation underlying birthweight. Interestingly, a similar effect size (0.226 SD per 500 g birthweight increase; p<0.05) was observed in the within-pair analysis, which controls for all shared influences within a twin pair. Conclusion DNA methylation is associated with individual differences in birthweight in a high-risk clinical population of MC twins, independent of shared genetic, familial or maternal influences.
M. Sulaiman, L. Franken, J. A. Spekman et al.· medRxiv· 0 citations
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.· medRxiv· 0 citations
