Commentary: The Seven Plagues of Epigenetic Epidemiology
Commentary: The Seven Plagues of Epigenetic Epidemiology
In many respects, large comprehensively phenotyped and longitudinally sampled epidemiological studies, like the 1958 British birth cohort used in the current study, are an ideal resource for epigenetic epidemiology. In nearly all of these studies, however, whole blood is the only biological material that has been archived. Blood is a heterogeneous tissue and any DNA methylation difference between groups could be confounded by differences in the cellular composition of whole blood samples, for example, resulting from the immune response to sub-clinical infection. The good news is that fewer than perhaps expected DNA methylation differences exist between leucocyte types, and controlling for cellular heterogeneity may be possible in biobanks with a simple blood cell count. Whether the latter is sufficient (and under which circumstances it is not), however, remains to be established. Epigenomic studies of separate cell types such as those being undertaken by the NIH Epigenomic Roadmap Initiative and the European Union Blueprint consortium are currently generating reference epigenomes of haematopoietic cells that will be of great utility in this regard. When moving beyond associations with environmental exposures to epigenetic associations with phenotypes, a key question for epigenetic epidemiology concerns the extent to which easily accessible peripheral tissues (such as blood) can be used to ask questions about inter-individual phenotypic variation manifest in inaccessible tissues such as the brain, visceral fat and other internal organs and tissues. Cross-tissue comparisons of the methylome within the same individual are currently underway to establish the relationship between epigenetic patterns in blood with other tissues. Although these analyses are crucial, the results may not be generally applicable; higher inter-tissue concordance may be present for DNA methylation changes induced early in development (and potentially propagated soma-wide) than for changes occur during ageing that are more likely to remain tissue specific. Efforts to obtain biopsies (subcutaneous fat, muscle, etc.) and post-mortem material in subsets of longitudinal biobanks will greatly increase their value for epigenetic studies, despite the problems associated with cellular heterogeneity that also hold for such samples.
Whatever We Do, It May Never be Enough to Fully Account for Epigenetic Differences Between Tissues and Cells
In many respects, large comprehensively phenotyped and longitudinally sampled epidemiological studies, like the 1958 British birth cohort used in the current study, are an ideal resource for epigenetic epidemiology. In nearly all of these studies, however, whole blood is the only biological material that has been archived. Blood is a heterogeneous tissue and any DNA methylation difference between groups could be confounded by differences in the cellular composition of whole blood samples, for example, resulting from the immune response to sub-clinical infection. The good news is that fewer than perhaps expected DNA methylation differences exist between leucocyte types, and controlling for cellular heterogeneity may be possible in biobanks with a simple blood cell count. Whether the latter is sufficient (and under which circumstances it is not), however, remains to be established. Epigenomic studies of separate cell types such as those being undertaken by the NIH Epigenomic Roadmap Initiative and the European Union Blueprint consortium are currently generating reference epigenomes of haematopoietic cells that will be of great utility in this regard. When moving beyond associations with environmental exposures to epigenetic associations with phenotypes, a key question for epigenetic epidemiology concerns the extent to which easily accessible peripheral tissues (such as blood) can be used to ask questions about inter-individual phenotypic variation manifest in inaccessible tissues such as the brain, visceral fat and other internal organs and tissues. Cross-tissue comparisons of the methylome within the same individual are currently underway to establish the relationship between epigenetic patterns in blood with other tissues. Although these analyses are crucial, the results may not be generally applicable; higher inter-tissue concordance may be present for DNA methylation changes induced early in development (and potentially propagated soma-wide) than for changes occur during ageing that are more likely to remain tissue specific. Efforts to obtain biopsies (subcutaneous fat, muscle, etc.) and post-mortem material in subsets of longitudinal biobanks will greatly increase their value for epigenetic studies, despite the problems associated with cellular heterogeneity that also hold for such samples.
