Epigenome-wide association (EWA) studies as a new frontier

As we’ve stated before many times, multifactorial traits are the result of contributions from many genes (DNA sequence), from epigenetics (DNA-methylation, RNA-interference, histone modifications, chromatin remodeling––independent of DNA sequence changes), and environmental effects. Today we have robust genome-wide association (GWA), whole-genome sequencing (WGS), and whole exome sequencing (WES or WXS) studies in the search for DNA alterations correlated to a given trait. Whole-genome assays for DNA-methylation and RNA-interference are improving all the time. Whole-genome assays for histone modifications and chromatin remodeling remain to be developed because these process remain very poorly understood.

Epigenome-wide association (EWA) studies represent the best means of applying genome-wide assays to identify molecular events that could be associated with human phenotypes independent of DNA sequence changes. The epigenome is especially intriguing as a target for study, because epigenetic regulatory processes are, by definition, heritable from parent to daughter cells, and these processes are found to have transcriptional regulatory properties. As such, the epigenome is an attractive candidate for mediating long-term responses to cellular stimuli––such as environmental effects modifying disease risk. Because each cell type has its own distinct epigenome, and we have ~200 different types of cells and these cells exist in ~20 different types of structures or organs, in theory there are perhaps as many as 4,000 unique epigenomes in the human body.

Such epigenomic studies represent a broader category of disease -Omics, which suffer from multiple problems in design and execution that (to date) severely limit their interpretability. In the attached report, authors define many of the problems with current epigenomic studies and propose solutions that can be applied to allow this and other disease -Omics studies to achieve their potential for generating valuable insights.

PLoS Genet  2o16; 12: e1006105

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