Enlarged Leukocyte Referent Libraries can Explain Additional Variance in Blood-Based Epigenome-Wide Association Studies

Abstract

Aim: We examined whether variation in blood-based epigenome-wide association studies could be more completely explained by augmenting existing reference DNA methylation libraries. Materials & methods: We compared existing and enhanced libraries in predicting variability in three publicly available 450K methylation datasets that collected whole-blood samples. Models were fit separately to each CpG site and used to estimate the additional variability when adjustments for cell composition were made with each library. Results: Calculation of the mean difference in the CpG-specific residual sums of squares error between models for an arthritis, aging and metabolic syndrome dataset, indicated that an enhanced library explained significantly more variation across all three datasets (p < 10^-3). Conclusion: Pathologically important immune cell subtypes can explain important variability in epigenome-wide association studies done in blood.

Keywords::

• 450K methylation library
• aging
• arthritis
• cell mixture deconvolution
• cellular heterogeneity
• confounding
• differentially methylated regions
• DNA methylation
• epigenome-wide association study
• inflammation
• lymphocytes

Acknowledgements

The authors would like to thank the authors whose publicly available datasets have helped us to construct our optimal 450K reference library. The authors acknowledge and thank the helpful suggestions and discussions of R Butler.

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/full/10.2217/epi-2016-0037

Financial & competing interests disclosure

J Wiencke was supported by the Robert Magnin Newman endowment for Neurooncology. This work was also supported by the NIH grants: (1KL2TR000119 to DC Koestler) and the Kansas IDeA Network of Biomedical Research Excellence (K-INBRE) Bioinformatics Core supported in part by the National Institute of General Medical Science award P20GM103418. 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.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

J Wiencke was supported by the Robert Magnin Newman endowment for Neurooncology. This work was also supported by the NIH grants: (1KL2TR000119 to DC Koestler) and the Kansas IDeA Network of Biomedical Research Excellence (K-INBRE) Bioinformatics Core supported in part by the National Institute of General Medical Science award P20GM103418. 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.