Maternal BMI associations with cord blood DNA methylation and mid-childhood adiposity

BACKGROUND: Childhood obesity is common and associated with adverse health outcomes. Fetal programming via epigenetics is a potential mechanism underlying its pathogenesis. We conducted an epigenome-wide association study (EWAS) on cord blood DNA to identify DNA methylation sites that may mediate the association of maternal body mass index (BMI) with offspring adiposity using data from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and its follow-up study (HAPO FUS). HAPO was a prospective, multicenter, international observational study that recruited pregnant women between 2000 and 2006 for glucose tolerance testing; cord blood was collected at delivery and newborn anthropometrics were obtained. The HAPO FUS was conducted from 2013 to 2016, where the 10-14 year-old offspring underwent measures of body composition, anthropometrics, and a fasting glucose tolerance test. Eligibility for HAPO FUS included gestational age at delivery ≥ 37 weeks without major neonatal malformations. There were 3,243 samples with cord blood DNA methylation (cbDNAm) data; mean child age at follow-up was 11.5 years. The present study used cord blood DNA to conduct methylation profiling using the Infinium MethylationEPIC 850 K BeadChip. Linear regression models were used to test the association between maternal BMI and cbDNAm levels adjusting for population substructure, cell count, maternal and child co-variates; multiple testing was accounted for using Bonferroni correction. Mediation analysis tested if cbDNAm CpG sites that were associated (Bonferroni P < 0.05) with maternal BMI explained the known association between maternal BMI and child BMI. RESULTS: This analysis included 3,116 mother-child pairs, 48% White, 21% Asian, 19% Black, 12% Hispanic and < 1% other race/ethnicity self-identified by the mother; 36% of mothers and 28.3% of children had an overweight or obese BMI. Maternal BMI was associated with DNAm at 7 CpG sites following adjustment including: cg00579423, cg07138793, cg12188424, cg19345626, cg20020844, cg02988288 and cg26974062. The 2 CpG sites on the TXNIP gene have been identified in previous EWAS of glucose metabolism and diabetes. Cord blood DNA methylation at cg20020844 (SP6) demonstrated mediation of 1.2% of the association between maternal BMI and child BMI z-score. CONCLUSIONS: Exposure to maternal obesity in utero and subsequent differential methylation present at birth may contribute to the prenatal programing of childhood obesity.