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

• Type of Material: Article
• Authors: Linda Dieckmann, Max Planck Inst Psychiat; Cristiana Cruceanu, Max Planck Inst Psychiat; Marius Lahti-Pulkkinen, University of Helsinki; Jari Lahti, University of Helsinki; Tuomas Kvist, University of Helsinki; Hannele Laivuori, University of Helsinki; Sara Sammallahti, University of Helsinki; Pia M Villa, Tampere University Hospital; Sanna Suomalainen-Koenig, Helsinki University Central Hospital; Rebecca C Rancourt, Humboldt-Universität Zu Berlin; Andreas Plagemann, Humboldt-Universität Zu Berlin; Wolfgang Henrich, Humboldt-Universität Zu Berlin; Johan G Eriksson, University of Helsinki; Eero Kajantie, Finnish Institute for Health and Welfare; Sonja Entringer, Freie Universität Berlin; Thorsten Braun, Freie Universität Berlin; Katri Räikkönen, University of Helsinki; Elisabeth Binder, Emory University; Darina Czamara, Max Planck Institute of Psychiatry
• Language: English
• Date: 2022-02-01
• Publisher: SPRINGER BASEL AG
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1007/s00018-021-04091-3
• Title of Journal or Parent Work: CELLULAR AND MOLECULAR LIFE SCIENCES
• Volume: 79
• Issue: 2
• Start Page: 115
• End Page: 115
• Grant/Funding Information: AP and TB disclose receipt of financial support for the research, authorship, and/or publication of this article, supported by DFG (BR2925/3-1,-2,-3 and PL241/8-2,-3). EK reports support from Academy of Finland, Foundation for Pediatric Research, Sigrid Juselius Foundation and Novo Nordisk Foundation.; Open Access funding enabled and organized by Projekt DEAL. The ITU study has been funded by the Academy of Finland (Award numbers: 1284859, 12848591, 312670 and 1324596) and the Finnish Diabetes Foundation.; The PREDO Study has been funded by the Academy of Finland (JL: 311617 and 269925, KR: 1312670 ja 128789 1287891), EraNet Neuron, EVO (a special state subsidy for health science research), University of Helsinki Research Funds, the Signe and Ane Gyllenberg foundation, the Emil Aaltonen Foundation, the Finnish Medical Foundation, the Jane and Aatos Erkko Foundation, the Novo Nordisk Foundation, the Päivikki and Sakari Sohlberg Foundation, Juho Vainio foundation, Yrjö Jahnsson foundation, The Finnish Society of Sciences and Letters, Jalmari and Rauha Ahokas foundation, Sigrid Juselius Foundation granted to members of the Predo study board. ML-P receives funding from the Academy of Finland, University of Helsinki Funds.
• Keywords: ANTENATAL BETAMETHASONE TREATMENT; Cell Biology; Science & Technology; EPIGENOME-WIDE ASSOCIATION; Human placenta; DEVELOPMENTAL ORIGINS; DNA methylation; SINGLE COURSE; Biochemistry & Molecular Biology; Reference-free deconvolution; EPIGENETICS; Reference-based deconvolution; Chorionic villi; Life Sciences & Biomedicine; PACKAGE; QUANTILE NORMALIZATION; SAMPLES; DECONVOLUTION; Cell type estimation
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Obstetrics and Gynecology

Abstract

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.