Abstract
BackgroundBirthweight marks an important milestone of health across the lifespan, including cardiometabolic disease risk in later life. The placenta, a transient organ at the maternal-fetal interface, regulates fetal growth. Identifying genetic loci where DNA methylation in placenta is associated with birthweight can unravel genomic pathways that are dysregulated in aberrant fetal growth and cardiometabolic diseases in later life.ResultsWe performed placental epigenome-wide association study (EWAS) of birthweight in an ethnic diverse cohort of pregnant women (n = 301). Methylation at 15 cytosine-(phosphate)-guanine sites (CpGs) was associated with birthweight (false discovery rate (FDR) < 0.05). Methylation at four (26.7%) CpG sites was associated with placental transcript levels of 15 genes (FDR < 0.05), including genes known to be associated with adult lipid traits, inflammation and oxidative stress. Increased methylation at cg06155341 was associated with higher birthweight and lower FOSL1 expression, and lower FOSL1 expression was correlated with higher birthweight. Given the role of the FOSL1 transcription factor in regulating developmental processes at the maternal-fetal interface, epigenetic mechanisms at this locus may regulate fetal development. We demonstrated trans-tissue portability of methylation at four genes (MLLT1, PDE9A, ASAP2, and SLC20A2) implicated in birthweight by a previous study in cord blood. We also found that methylation changes known to be related to maternal underweight, preeclampsia and adult type 2 diabetes were associated with lower birthweight in placenta.ConclusionWe identified novel placental DNA methylation changes associated with birthweight. Placental epigenetic mechanisms may underlie dysregulated fetal development and early origins of adult cardiometabolic diseases.Clinical trial registrationClinicalTrials.gov, NCT00912132
Highlights
Birthweight marks an important milestone of health across the lifespan, including cardiometabolic disease risk in later life
Data set We used DNA methylation data measured using Illumina’s Infinium Human Methylation450 Beadchip (Illumina Inc., San Diego, CA) on placentas obtained at delivery from 301 pregnant women who participated in the NICHD Fetal Growth Studies–Singletons [28, 29]
For Cytosine-phosphate-guanine genomic site (CpG) known to be associated with childhood/adult cardiometabolic traits in previous epigenome-wide association study (EWAS) (including myocardial infarction (n = 189 CpGs), lipid traits (n = 792 CpGs), blood pressure-related traits (n = 18 CpGs), type 2 diabetes (n = 5672 CpGs), and body mass index (n = 1079 CpGs); Additional Table 7), we examined whether DNA methylation at these CpGs in placenta was associated with birthweight
Summary
Birthweight marks an important milestone of health across the lifespan, including cardiometabolic disease risk in later life. Identifying genetic loci where DNA methylation in placenta is associated with birthweight can unravel genomic pathways that are dysregulated in aberrant fetal growth and cardiometabolic diseases in later life. Complex interplays between genetic and environmental influences play important roles in regulating fetal growth and development [4]. Epigenetic mechanisms such as DNA methylation may represent the regulatory links between genetic and environmental influences on birthweight [5]. Identifying DNA methylation loci that are associated with birthweight can give clues to detect molecular biomarkers of aberrant fetal growth and cardiometabolic diseases in later life. Compromised placental function has often been associated with aberrant fetal growth [7] and risk of cardiometabolic diseases in later life [8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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 call
