Grasping nettles: cellular heterogeneity and other confounders in epigenome-wide association studies.

Platform technologies for measurement of CpG methylation at multiple loci across the genome have made ambitious epigenome-wide association studies affordable and practicable. In contrast to genetic studies, which estimate the effects of structural changes in DNA, and transcriptomic studies, which measure genomic outputs, epigenetic studies can access states of regulation of genome function in particular cells and in response to specific stimuli. Although many factors complicate the interpretation of epigenetic variation in human disease, cell-specific methylation patterns and the cellular heterogeneity present in peripheral blood and tissue biopsies are anticipated to cause the most problems. In this review, we suggest that the difficulties may be exaggerated and we explore how cellular heterogeneity may be embraced with appropriate study designs and analytical tools. We further suggest that systematic mapping of the loci influenced by age, sex and genetic polymorphisms will bring important biological insights as well as improved control of epigenome-wide association studies.