Genetic studies and in particular genome-wide association studies revealed numerous DNA sequence variants contributing to the risk of human disease. This provided important new insights in the biological processes underlying many common diseases. Together, however, the sequence variants explain only a small proportion of the disease risk. Are we overlooking something? Yes, more and more researchers say: the epigenome. In a paper in the FASEB Journal (April 2010), Bas Heijmans from the Leiden University Medical Center and member of the Netherlands Consortium for Healthy Ageing and his colleagues at the LUMC and Free University of Amsterdam (VU) answer the question how the role of the epigenome in disease can effectively be investigated in large-scale studies.
The epigenome refers to all the molecular modifications and packaging of the DNA that determine whether genes are poised to be transcribed or not. In a simplified analogy: the DNA provides the dictionary, the epigenome which words are used and how often. Although the potential importance of the epigenome for human disease is well-recognized, there is a lot of uncertainty on how to approach studies on the topic. In contrast to the DNA sequence, the epigenome can in principal be unique for every cell and, to make it worse, may change over time. This would render many of the large biobanks established for genetic research useless for epigenome research. Frequently, only a blood sample is available and not the tissues directly involved in disease. Moreover, the diseases of interest will occur many years after obtaining the sample.
Heijmans and colleagues studied DNA methylation, the best-characterized layer of epigenomic information. ‘We were surprised to see how stable DNA methylation is for most genes over a 20-year period. Also, we found that methylation in blood was a good marker for that in a completely unrelated tissue for various genes’, Heijmans says. The results suggest that powerful epigenome studies may be feasible very much like we witnessed in genetics provided that studies are designed with great care. That genetic and epigenome studies may have more in common than expected was illustrated by the patterns in DNA methylation that were reminiscent of that observed for genetic variation (linkage disequilibrium), a phenomenon that greatly accelerated discoveries in genetic studies. Heijmans is optimistic: ‘The coming years studies that integrate epigenomic and genetic data may well reveal genomic risk factors that are more powerful than the current ones solely based on DNA sequence variation.’
The article: Talens RP, Boomsma DI, Tobi EW, Kremer D, Jukema JW, Willemsen G, Putter H, Slagboom PE, Heijmans BT. Variation, patterns and temporal stability of DNA methylation: considerations for epigenetic epidemiology. FASEB J 2010
This work was financially supported by The Netherlands Heart Foundation, The Netherlands Organization for Scientific Research (NWO), the EU-funded Network of Excellence LifeSpan, The Netherlands Consortium for Healthy Ageing (NCHA) and others.