Genetic variants influence on the placenta regulatory landscape

Abstract

Background: From genomic association studies, quantitative trait loci analysis, and epigenomic mapping, it is evident that significant efforts are necessary to define geneticepigenetic interactions and understand their role in disease susceptibility and progression. For this reason, an analysis of the effects of genetic variation on gene expression and DNA methylation in human placentas at high resolution and wholegenome coverage will have multiple mechanistic and practical implications.Results: By producing and analyzing DNA sequence variation (n=303), DNA methylation (n=303) and mRNA expression data (n=80) from placentas from healthy women, we investigate the regulatory landscape of the human placenta and offer analytical approaches to integrate different types of genomic data and address some potential limitations of current platforms. We distinguish two profiles of interaction between expression and DNA methylation, revealing linear or bimodal effects, reflecting differences in genomic context, transcription factor recruitment, and possibly cell subpopulations.Conclusions: These findings help to clarify the interactions of genetic, epigenetic, and transcriptional regulatory mechanisms in normal human placentas. They also provide strong evidence for genotype-driven modifications of transcription and DNA methylation in normal placentas. In addition to these mechanistic implications, the data and analytical methods presented here will improve the interpretability of genome-wide and epigenome-wide association studies for human traits and diseases that involve placental functions. Author summaryThe placenta is a critical organ playing multiple roles including oxygen and metabolite transfer from mother to fetus, hormone production, and vascular perfusion. With this study, we aimed to deliver a placenta-specific regulatory map based on a combination of publicly available and newly generated data. To complete this reference, we obtained genotype information (n=303), DNA methylation (n=303) and expression data (n=80) for placentas from healthy women. Our analysis of methylation and expression quantitative trait loci (QTLs) and correlations between methylation and expression data were designed to identify fundamental associations between genome, transcriptome, and epigenome in this key fetal organ. The results provide high-resolution genetic and epigenetic maps specific to the placenta based on a representative ethnically diverse cohort. As interest and efforts are growing to better understand the etiology of placental disease and the impact of the environment on placental function these data will provide a reference and enhance future investigations.

Placental DNA methylation signatures of maternal smoking during pregnancy and potential impacts on fetal growth

“…It is possible that MSDP, genetic variation, and placental DNAm in these regions yield additive or interactive effects on birth outcomes; prior studies have addressed this question in blood 52,53 . Additionally, while our MSDP-associated CpGs are in similar genomic regions (1 Mb windows) with birth outcome SNPs, very few of our CpGs (9 of 1224) and very few of the birth outcome SNPs (3 of 324) are known placental mQTLs 32,33 .…”

“…We also explored whether our MSDP-associated CpGs may be biased by methylation quantitative trait loci (mQTLs), in which SNPs influence the methylation levels at nearby CpGs. Two studies have examined this question in human placenta, identifying 866 32 and 4,342 33 placental mQTLs. Our findings did not appear to be biased by genetic variation as only 9 of the 1,224 MSDP-associated CpGs are previously characterized placental mQTLs.…”

Cell-specific Characterization of the Placental Methylome

“…Supporting this, a signi cant role for genetic control of placental DNAm variation was recently characterized by Delahaye et al. (22). These studies have contributed to our understanding of the unique epigenetics of the placenta, but it remains unclear if these features are maintained in all constituent placental cell types or are con ned to speci c ones.…”

Cell-specific Characterization of the Placental Methylome

“…It is possible that cellular and genetic heterogeneity can contribute to polymorphic imprinting, as well as variability in DNAm generally. Supporting this, a signi cant role for genetic control of placental DNAm variation was recently characterized by Delahaye et al (22). These studies have contributed to our understanding of the unique epigenetics of the placenta, but it remains unclear if these features are maintained in all constituent placental cell types or are con ned to speci c ones.…”