Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 79, Issue 2, Pages -Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-021-04091-3
Keywords
Cell type estimation; DNA methylation; Human placenta; Chorionic villi; Reference-based deconvolution; Reference-free deconvolution
Categories
Funding
- Academy of Finland [1284859, 12848591, 312670, 1324596, 311617, 269925, 1312670 ja 128789 1287891]
- Finnish Diabetes Foundation
- University of Helsinki Research Funds
- Signe and Ane Gyllenberg foundation
- Emil Aaltonen Foundation
- Finnish Medical Foundation
- Jane and Aatos Erkko Foundation
- Novo Nordisk Foundation
- Paivikki and Sakari Sohlberg Foundation
- Juho Vainio foundation
- Yrjo Jahnsson foundation
- Finnish Society of Sciences and Letters
- Sigrid Juselius Foundation
- University of Helsinki Funds
- DFG [BR2925/3-1, PL241/8-2, BR2925/3-2, BR2925/3-3, PL241/8-3]
- Foundation for Pediatric Research
- Jalmari and Rauha Ahokas foundation
- EraNet Neuron
- EVO (a special state subsidy for health science research)
- Academy of Finland (AKA) [269925, 312670, 311617, 312670, 311617, 269925] Funding Source: Academy of Finland (AKA)
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The placenta plays a central role in early development and has implications for disease risk. DNA methylation studies of the human placenta can provide insights into its function. This study compares different methods of estimating cell types in placental DNA samples and finds that using a reference-based approach gives more accurate results than a reference-free approach.
The placenta is a central organ during early development, influencing trajectories of health and disease. DNA methylation (DNAm) studies of human placenta improve our understanding of how its function relates to disease risk. However, DNAm studies can be biased by cell type heterogeneity, so it is essential to control for this in order to reduce confounding and increase precision. Computational cell type deconvolution approaches have proven to be very useful for this purpose. For human placenta, however, an assessment of the performance of these estimation methods is still lacking. Here, we examine the performance of a newly available reference-based cell type estimation approach and compare it to an often-used reference-free cell type estimation approach, namely RefFreeEWAS, in placental genome-wide DNAm samples taken at birth and from chorionic villus biopsies early in pregnancy using three independent studies comprising over 1000 samples. We found both reference-free and reference-based estimated cell type proportions to have predictive value for DNAm, however, reference-based cell type estimation outperformed reference-free estimation for the majority of data sets. Reference-based cell type estimations mirror previous histological knowledge on changes in cell type proportions through gestation. Further, CpGs whose variation in DNAm was largely explained by reference-based estimated cell type proportions were in the proximity of genes that are highly tissue-specific for placenta. This was not the case for reference-free estimated cell type proportions. We provide a list of these CpGs as a resource to help researchers to interpret results of existing studies and improve future DNAm studies of human placenta.
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