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A cell type enrichment analysis tool for brain DNA methylation data (CEAM).

Joshua Müller1, Valentin T Laroche1, Jennifer Imm2

  • 1Department of Psychiatry and Neuropsychology, Mental Health and Neuroscience Research Institute (MHeNs), Maastricht University, Maastricht, The Netherlands.

Epigenetics
|December 22, 2025
PubMed
Summary
This summary is machine-generated.

We developed CEAM, a new tool to analyze cell type-specific DNA methylation changes in bulk tissue. This method enhances epigenome-wide association studies (EWAS) by improving accuracy in neurodegenerative disease research.

Keywords:
DNA methylationbraincell typeepigenomicsneurodegenerative diseases

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Area of Science:

  • Neuroscience
  • Genetics
  • Computational Biology

Background:

  • DNA methylation (DNAm) patterns are cell type-specific, but bulk tissue analysis in epigenome-wide association studies (EWAS) can obscure these crucial details.
  • Current computational tools for identifying cell type-specific DNAm changes face limitations due to the accuracy of cell type deconvolution algorithms.

Purpose of the Study:

  • Introduce CEAM (Cell-type Enrichment Analysis for Methylation), a robust framework for cell type enrichment analysis in DNA methylation data.
  • To provide an interpretable and accurate method for analyzing cell type-specific DNAm from bulk tissue EWAS data.

Main Methods:

  • CEAM utilizes over-representation analysis with cell type-specific CpG panels derived from sorted brain nuclei.
  • CpG panels were validated using simulated data and published EWAS results from Alzheimer's disease, Lewy body disease, and multiple sclerosis.
  • The framework was tested for resilience to cell type composition shifts and varying accuracy in upstream modeling.

Main Results:

  • CEAM demonstrated robustness against shifts in cell type composition, a common EWAS confounder.
  • The tool remained accurate across various differentially methylated positions when cell type composition was adequately modeled.
  • Application to neurodegenerative disease EWAS data revealed biologically relevant enrichment patterns consistent with known disease mechanisms.

Conclusions:

  • CEAM offers a reliable and interpretable method for uncovering cell type-specific DNA methylation patterns in bulk tissue.
  • The framework enhances the biological relevance and accuracy of EWAS findings, particularly in neurodegenerative disease research.
  • CEAM is available as a public Shiny app for accessible analysis of cell type-specific DNAm changes.