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*

*Corresponding author for this work

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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.

Original languageEnglish
Article number115
JournalCellular and Molecular Life Sciences
Volume79
Issue number2
DOIs
Publication statusPublished - 3 Feb 2022

Bibliographical note

Funding Information:
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. 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.

Funding Information:
We would like to thank all of the midwives, obstetricians, and other medical staff, laboratory and research personnel, and administrative staff working in hospitals, antenatal and child wellbeing clinics, municipalities, national registers, and other institutions, whose efforts have made this research possible. We thank the midwifes, Dr. A. Gusarova, Dr. F. Braun-Tavares and A. K. Hardt at the Department for Obstetrics, Charit? for valuable assistance in recruiting study participants. We also thank L. Ehrlich at the Department for Obstetrics, Charit? for her assistance in placental tissue preparation. The PREDO study would not have been possible without the dedicated contribution of the PREDO study group members: E Ham?l?inen, E Kajantie, H Laivuori, PM Villa, A-K Pesonen, A Aitokallio-Tallberg, A-M Henry, VK Hiilesmaa, T Karipohja, R Meri, S Sainio, T Saisto, S Suomalainen-Konig, V-M Ulander, T Vaitilo (Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland), L Keski-Nisula, Maija-Riitta Orden (Kuopio University Hospital, Kuopio Finland), E Koistinen, T Walle, R Solja (Northern Karelia Central Hospital, Joensuu, Finland), M Kurkinen (P?ij?t-H?me Central Hospital, Lahti, Finland), P.Taipale. P Staven (Iisalmi Hospital, Iisalmi, Finland), J Uotila (Tampere University Hospital, Tampere, Finland). The ITU study would not have been possible without the dedicated contribution of the staff at the Helsinki and Uusimaa Hospital District Feto-maternal Medical Center and delivery hospitals. We further thank S. Sauer, M. K?del, M. Rex-Haffner and A. Tontsch for their technical support. We wish to express our deepest gratitude to all women and children who participated in the studies. Furthermore, we would like to thank Mark de Rooij for his support as regards the use of the R package xvalglms and enabling further functionalities in this package.

Funding Information:
EB is the coinventor of FKBP5: a novel target for antidepressant therapy, European Patent no. EP 1687443 B1, and receives a research grant from Böhringer Ingelheim for a collaboration on functional investigations of FKBP5. Otherwise, the authors declare that they have no competing interests.

Publisher Copyright:
© 2022, The Author(s).

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