Background

Both genome-wide association studies (GWAS) and epigenome-wide association studies (EWAS) are aiming to discover molecular signs for diseases, which possibly can be helpful for future therapeutic intervention strategies. The most prominently used tissue in association studies on humans is venous blood. In contrast to the unchangeable genotype, epigenetic DNA methylation is more variable. Methylation is affected not only by a subject’s constitution such as age, gender, ethnicity, genotype, lifestyle and health status, but is also determined by tissue-specific cell types.

Methods

PubMed, published before 2017, was researched, documenting the importance of epigenetic analyses on single cell types instead of whole blood in EWAS.

Results

Initial studies documented that stressor-induced, mostly marginal, DNA methylation changes in whole-blood samples (< 5% methylation difference) may rely not on uniform distribution of that methylation shift among each blood cell type, but on strongly altered methylation (> 20%) in single cell types. The effect size in single cell types enables the performance of epigenome-wide studies on replicated smaller cohorts, in contrast to the requirement of larger international consortium-based approaches.

Conclusions

Therefore, the identification of a specific cell type that is responsible for association between DNA methylation in whole blood with the phenotype of interest, has to be a prioritized experimental approach in association studies. This is a key prerequisite for constructive interpretation of epigenetic signs in the context of diverse biological function of the tissue blood, for detection of causality link between methylation and phenotype and for establishment of valuable clinical biomarkers and therapeutic targets.