Epigenomic Studies of Twins and Brain Diseases

It has been generally accepted that complex diseases are caused by genetic and environmental factors; however, both genetic and epidemiological research programs are facing significant difficulties in explaining the etiopathogenesis of complex diseases. It has been suggested lately that inclusion of putative epigenetic disease mechanisms may enable one to bypass the limitations of the traditional research strategy and allow the integration of genetic and environmental risk factors into a new theoretical framework. In this thesis, we analyzed normal human twins to demonstrate that monozygotic twins exhibit numerous epigenetic differences, not all of which were caused by environmental factors. We also showed that dizygotic twins were epigenetically even more divergent than monozygotic twins, which suggests that heritability may not be an exclusive function of DNA, but may also extend to epigenetic factors. In order to address the role of epigenetic factors in diseases, we performed large-scale epigenomic studies of singletons and twins who were discordant for major depressive disorder and Alzheimer's disease. We investigated DNA modification patterns across multiple tissue types and applied a series of innovative analytical techniques to explore the various aspects of DNA modification differences between normal and diseased individuals. In the major depressive disorder study, we investigated the confounding effects of disease heterogeneity and the age-dependent changes in variation of DNA modification. We uncovered several unknown epigenetic facets, such as long-range epigenetic effects, epigenetic outliers, and changes in the epigenomic networks. In the Alzheimer's disease study, we found evidence for loss of epigenetic uniqueness in the aging brain, which progresses faster in patients with dementia. This work adds to the notion that epigenomic studies can transform our understanding regarding the origin of complex diseases.Ph