Genetic and in utero environmental contributions to DNA methylation variation in placenta.

Genetic and prenatal environmental factors shape fetal development and cardiometabolic health in later life. A key target of genetic and prenatal environmental factors is the epigenome of the placenta, an organ that is implicated in fetal growth and diseases in later life. This study had two aims: (1) to identify and functionally characterize placental variably methylated regions (VMRs), which are regions in the epigenome with high inter-individual methylation variability; and (2) to investigate the contributions of fetal genetic loci and 12 prenatal environmental factors (maternal cardiometabolic-,psychosocial-, demographic- and obstetric-related) on methylation at each VMR. Akaike's information criterion was used to select the best model out of four models [prenatal environment only, genotype only, additive effect of genotype and prenatal environment (G + E), and their interaction effect (G × E)]. We identified 5850 VMRs in placenta. Methylation at 70% of VMRs was best explained by G × E, followed by genotype only (17.7%), and G + E (12.3%). Prenatal environment alone best explained only 0.03% of VMRs. We observed that 95.4% of G × E models and 93.9% of G + E models included maternal age, parity, delivery mode, maternal depression or gestational weight gain. VMR methylation sites and their regulatory genetic variants were enriched (P < 0.05) for genomic regions that have known links with regulatory functions and complex traits. This study provided a genome-wide catalog of VMRs in placenta and highlighted that variation in placental DNA methylation at loci with regulatory and trait relevance is best elucidated by integrating genetic and prenatal environmental factors, and rarely by environmental factors alone.