Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium

Abstract

Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1 kg/m2), P < 1.06 × 10−7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for a6causal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites. In conclusion, this well-powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large-scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.

Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age

“…However, we cannot rule out the possibility that some overlapping CpGs could be involved in biologic pathways linking smoking to the well-established consequence of shorter gestational length [94]. Other potential confounders not accounted for in this study such as maternal obesity and alcohol intake may influence offspring DNA methylation although we have found in the PACE consortium that their impact on methylation [95,96] is very modest compared with maternal smoking in pregnancy which was included in our models.…”

Impact of pregravid obesity on maternal and fetal immunity: Fertile grounds for reprogramming

“…83 Similarly, maternal BMI has been linked to methylation levels of several loci in the cord blood, the majority of which persist into adolescence independent of paternal BMI and gestational weight gain. 203,204 Studies focusing on immune cells have demonstrated that high maternal BMI is inversely correlated with methylation levels within the promoter of inflammatory genes in cord blood mononuclear cells 205 that persisted for up to 3 years of age. 206 Recent studies carried out using targeted bisulfite sequencing in purified cord blood monocytes demonstrated that pregravid maternal obesity is associated with DNA hypomethylation, particularly at promoters of transcription factors such as PPARG that are associated with a dampened transcriptional responses to LPS.…”

The International Childhood Cancer Cohort Consortium (I4C): A research platform of prospective cohorts for studying the aetiology of childhood cancers

“…members have begun cataloguing-omics signatures of early-life factors that could be associated with CC. 29,30 These signatures will be analysed across the different I4C cohorts with available biological samples. This work will complement the I4C questionnaire-based epidemiological investigations and may provide mechanistic insights into CC aetiology.…”