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/m 2 ), P < 1.06 Â 10 À7 ) 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.

Maternal Birth Weight and BMI Mediate the Transgenerational Effect of Grandmaternal BMI on Grandchild’s Birth Weight

“…One candidate of the mechanisms is DNA methylation, which may memorize and transfer information on grandmaternal metabolism (BMI) or smoking to the next generation. Maternal BMI and smoking during pregnancy have been identified to be associated with differential DNA methylations in the offspring. It is possible that the influences of grandmaternal BMI and smoking on epigenetic changes can persist into later life of the mothers and then be transferred to the third generation.…”

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

“…Maternal hyperglycemia has been shown to decrease methylation of the leptin gene ( LEP ) in the offspring, contributing to high leptin levels in cord blood of babies born to obese mothers . 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 . 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 that persisted for up to 3 years of age .…”

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

“…A review paper describes the characteristics of the epigenome as a key component of foetal exposure in evaluating in utero exposures and childhood cancer risk . More recently, I4C members have begun cataloguing— omics signatures of early‐life factors that could be associated with CC . These signatures will be analysed across the different I4C cohorts with available biological samples.…”