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Genetics and Epigenetics

Placental DNA methylation changes associated with maternal prepregnancy BMI and gestational weight gain

International Journal of Obesity volume 44, pages 1406–1416 (2020)Cite this article

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Abstract

Background

Maternal obesity prior to or during pregnancy influences fetal growth, predisposing the offspring to increased risk for obesity across the life course. Placental epigenetic mechanisms may underlie these associations. We conducted an epigenome-wide association study to identify placental DNA methylation changes associated with maternal prepregnancy body mass index (BMI) and rate of gestational weight gain at first (GWG1), second (GWG2), and third trimester (GWG3).

Method

Participants of the NICHD Fetal Growth Studies with genome-wide placental DNA methylation (n = 301) and gene expression (n = 75) data were included. Multivariable-adjusted regression models were used to test the associations of 1 kg/m2 increase in prepregnancy BMI or 1 kg/week increase in GWG with DNA methylation levels. Genes harboring top differentially methylated CpGs (FDR P < 0.05) were evaluated for placental gene expression. We assessed whether DNA methylation sites known to be associated with BMI in child or adult tissues, were also associated with maternal prepregnancy BMI in placenta.

Results

Prepregnancy BMI was associated with DNA methylation at cg14568196[EGFL7], cg15339142[VETZ], and cg02301019[AC092377.1] (FDR P < 0.05, P ranging from 1.4 × 10−10 to 1.7 × 10−9). GWG1 or GWG2 was associated with DNA methylation at cg17918270[MYT1L], cg20735365[DLX5], and cg17451688[SLC35F3] (FDR P < 0.05, P ranging from 6.4 × 10−10 to 1.2 × 10−8). Both prepregnancy BMI and DNA methylation at cg1456819 [EGFL7] were negatively correlated with EGFL7 expression in placenta (P < 0.05). Several CpGs previously implicated in obesity traits in children and adults were associated with prepregnancy BMI in placenta. Functional annotations revealed that EGFL7 is highly expressed in placenta and the differentially methylated CpG sites near EGFL7 and VEZT were cis-meQTL targets in blood.

Conclusions

We identified placental DNA methylation changes at novel loci associated with prepregnancy BMI and GWG. The overlap between CpGs associated with obesity traits in placenta and other tissues in children and adults suggests that epigenetic mechanisms in placenta may give insights to early origins of obesity.

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Fig. 1: Correlation between DNA methylation at top significant CpG sites and expression of the corresponding gene.

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Data availability

The DNA methylation, genotype, and gene expression data are available through dbGaP with accession number phs001717.v1.p1.

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Acknowledgements

The authors acknowledge the research teams at all participating clinical centers for the NICHD Fetal Growth Studies, including Christina Care Health Systems, Columbia University, Fountain Valley Hospital, California, Long Beach Memorial Medical Center, New York Hospital, Queens, Northwestern University, University of Alabama at Birmingham, University of California, Irvine, Medical University of South Carolina, Saint Peters University Hospital, Tufts University, and Women and Infants Hospital of Rhode Island. The authors also acknowledge C-TASC and The EMMES Corporations in providing data and imaging support. Genotyping was performed in the Department of Laboratory Medicine and Pathology, University of Minnesota. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov).

Funding

This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contracts HHSN275200800013C; HHSN275200800002I; HHSN27500006; HHSN275200800003IC; HHSN275200800014C; HHSN275200800012C; HHSN275200800028C; HHSN275201000009C; HHSN27500008). In addition support was obtained from the National Institute on Minority Health and Health Disparities, and the National Institute of Diabetes and Digestive and Kidney Diseases.

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Authors and Affiliations

  1. Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

    Deepika Shrestha, Marion Ouidir, Tsegaselassie Workalemahu & Fasil Tekola-Ayele

  2. Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

    Xuehuo Zeng

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  1. Deepika Shrestha
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Contributions

FT-A conceived and designed this study; DS performed statistical analyses and wrote the draft paper. All authors contributed to interpretation of the results, provided critical intellectual content, and approved the final paper.

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Correspondence to Fasil Tekola-Ayele.

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Shrestha, D., Ouidir, M., Workalemahu, T. et al. Placental DNA methylation changes associated with maternal prepregnancy BMI and gestational weight gain. Int J Obes 44, 1406–1416 (2020). https://doi.org/10.1038/s41366-020-0546-2

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