DNA methylation loci in placenta associated with birthweight and expression of genes relevant for early development and adult diseases

Fasil Tekola-Ayele, Xuehuo Zeng, Marion Ouidir, Tsegaselassie Workalemahu, Cuilin Zhang, Fabien Delahaye, Ronald Wapner, Fasil Tekola-Ayele, Xuehuo Zeng, Marion Ouidir, Tsegaselassie Workalemahu, Cuilin Zhang, Fabien Delahaye, Ronald Wapner

Abstract

Background: Birthweight 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.

Results: We 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.

Conclusion: We 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 registration: ClinicalTrials.gov, NCT00912132.

Keywords: Birthweight; DNA methylation; Developmental origins of health and disease (DOHaD); Expression quantitative trait methylation (eQTM); Fetal growth; Placenta; Transcriptomics.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Distributions of associations between CpG sites in placenta and birthweight. a Manhattan plot. b Volcano plot. Horizontal red line marks FDR 0.05; red dots denote CpGs significantly associated with birthweight
Fig. 2
Fig. 2
Correlations between birthweight and placental expression of genes associated DNA methylation levels of birthweight-associated CpG sites. aFOSL1. bUBASH3A
Fig. 3
Fig. 3
Triangular relationship between DNA methylation at cg06155341, expression of FOSL1, and birthweight
Fig. 4
Fig. 4
Overlap in CpGs significantly associated with birthweight in placenta and adult traits. A Non-cardiometabolic adult diseases. B Maternal perinatal cardiometabolic conditions. C Cardiometabolic traits in adults. Gene and CpG names in red represent DNA methylation changes associated with increased risk of adult disease as well as lower birthweight. Gene and CpG names in blue represent DNA methylation changes associated with increased risk of adult disease and higher birthweight. SLE stands for systemic lupus erythematosus

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