Estimating cell-type-specific DNA methylation effects in heterogeneous cellular populations

Abstract

Aim: To develop a method for estimating cell-specific effects in epigenomic association studies in the presence of cell type heterogeneity. Materials & methods: We utilized Monte Carlo Expectation-Maximization algorithm with Metropolis–Hastings sampler to reconstruct the ‘missing’ cell-specific methylations and to estimate their associations with phenotypes free of confounding by cell type proportions. Results: Simulations showed reliable performance of the method under various settings including when the cell type is rare. Application to a real dataset recapitulated the directly measured cell-specific methylation pattern in whole blood. Conclusion: This work provides a framework to identify important cell groups and account for cell type composition useful for studying the role of epigenetic changes in human traits and diseases.

Keywords::

• cell-type-specific effect
• deconvolution
• DNA methylation
• epigenome-wide association study

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2020-0147

Y-CA Feng and L Liang conceived the method and YA Feng implemented the simulation and analysis with the help from Y Guo, GM Lathrop, C Laprise, MF Moffatt and WOCM Cookson provided methylation data from the IgE study, in which L Pain contributed in cells isolation and DNA isolation from cells. YA Feng wrote the manuscript and interpreted the results with L Liang All the co-authors provided feedback to the manuscript.

Financial & competing interests disclosure

We want to thank the following funding resources that supported data generation relevant to this work. Dr. Catherine Laprise is supported by the Canada Research Chair Program (CRC1) in Environment and Genetics of Respiratory Disorders and Allergy at the Québec Respiratory Health Network (QRHN), co-responsible of the Environment Genetics and Cancer axis. Her work was also funded through Centre de Recherche en Santé Durable (CIHR) Grant no. 8. Lucile Pain is supported by the Québec Respiratory Health Network’s PhD course. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

We want to thank the following funding resources that supported data generation relevant to this work. Dr. Catherine Laprise is supported by the Canada Research Chair Program (CRC1) in Environment and Genetics of Respiratory Disorders and Allergy at the Québec Respiratory Health Network (QRHN), co-responsible of the Environment Genetics and Cancer axis. Her work was also funded through Centre de Recherche en Santé Durable (CIHR) Grant no. 8. Lucile Pain is supported by the Québec Respiratory Health Network’s PhD course. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.