Abstract
Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from −183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10−7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10−74) and BMI in pregnancy (3/914, p = 1.13x10−3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.
Highlights
8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from −183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10−7)
We show that DNA methylation in neonatal blood is associated with birthweight and some of the differential methylation is observed in childhood and adolescence, but not in adulthood
We observed some enrichment of birthweight-associated cytosine-phosphate-guanine sites (CpGs) among sites that have previously been linked to smoking during pregnancy[14] and pre-pregnancy BMI15, consistent with the hypothesis that epigenetic pathways may underlie the observational associations of those prenatal exposures with birthweight[21,44,45]
Summary
8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from −183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10−7). Our overall conceptual framework in this study was that the intrauterine environment induces epigenetic alterations, which influence fetal growth and correlate with birthweight This is partly supported by previous large-scale epigenome-wide association studies (EWAS) that have reported associations of relevant maternal pregnancy exposures, including smoking, air pollution and BMI, with DNA methylation in offspring neonatal blood[14,15,16]. We (i) explore the overlap of identified cytosine-phosphate-guanine sites (CpGs) that are differentially methylated in relation to birthweight with those known to be associated with intrauterine exposure to smoking, famine and different levels of BMI and folate; (ii) associate DNA methylation at identified CpGs with gene expression and (iii) explore potential causal links with birthweight and later-life health using Mendelian randomization (MR)[22]. Potential causality of the associations needs to be studied further
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
