Could Epigenome Degeneration be a Cause for the Late Onset of Complex Disease Phenotypes?

Hans Bjornsson
Predoctoral Program in Human Genetics; Johns Hopkins University School of Medicine

The possibility that early exposures affect the epigenome in ways that later in life mediate complex disease predisposition is intriguing. However, if a disease causing epigenome is present at birth, why is there a lag period of about 50 years before disease occurs? One possibility is that the epigenome degenerates over time (because of age, environment or stochastic events) and that certain in utero exposures predispose to epigenomes that reach a disease state faster than others. In two recent publications we have suggested that common human disease is caused by a combination of epigenetic and genetic factors (CDGE model). We have summarized the many possible causes of epigenome variability (stochastic events, environment, age, parental epigenotype, DNA genotype(s) of either parents or offspring and parental environment) as well as the various ways epigenetic modifications might affect disease. Furthermore, we have contrasted the age-of onset of Mendelian disease (onset mainly before puberty) versus complex adult-onset disease (onset mainly after 50 years of age). We have simulated the expected Relative Risks (RR) and Population Attributable Risks (PAR) of disease phenotypes that were assumed to be either purely genetic (no epigenetic effect) or genetic and epigenetic (assuming that the epigenome degenerates with age). Interestingly, the simulated RR and PAR of the purely genetic disease phenotype are very similar to that of Mendelian disease but the RR and PAR of the genetic and epigenetic disease phenotype are closer to that of complex adult-onset disease.

REFERENCES

1: Bjornsson, HT, Cui, H, Gius, D, Fallin, MD, and Feinberg, AP. The new field of epigenomics: implications for cancer and other common disease research. Cold Spring Harb Symp Quant Biol 69: 447-456, 2004.

2: Bjornsson, HT, Fallin, MD, and Feinberg, AP. An integrated epigenetic and genetic approach to common human disease. Trends Genet 20: 350-358, 2004.