Reliability of a novel approach for reference-based cell type estimation in human placental DNA methylation studies

Linda Dieckmann, Cristiana Cruceanu, Marius Lahti-Pulkkinen, Jari Lahti, Tuomas Kvist, Hannele Laivuori, Sara Sammallahti, Pia M. Villa, Sanna Suomalainen-König, Rebecca C. Rancourt, Andreas Plagemann, Wolfgang Henrich, Johan G. Eriksson, Eero Kajantie, Sonja Entringer, Thorsten Braun, Katri Räikkönen, Elisabeth B. Binder, Darina Czamara

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    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.

    Original languageEnglish
    Article number115
    Issue number2
    Publication statusPublished - 3 Feb 2022
    Publication typeA1 Journal article-refereed


    • Cell type estimation
    • Chorionic villi
    • DNA methylation
    • Human placenta
    • Reference-based deconvolution
    • Reference-free deconvolution

    Publication forum classification

    • Publication forum level 2

    ASJC Scopus subject areas

    • Molecular Medicine
    • Molecular Biology
    • Pharmacology
    • Cellular and Molecular Neuroscience
    • Cell Biology


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