Epigenetics of discordant monozygotic twins: implications for disease

Abstract

Monozygotic (MZ) twins share nearly all of their genetic variants and many similar environments before and after birth. However, they can also show phenotypic discordance for a wide range of traits. Differences at the epigenetic level may account for such discordances. It is well established that epigenetic states can contribute to phenotypic variation, including disease. Epigenetic states are dynamic and potentially reversible marks involved in gene regulation, which can be influenced by genetics, environment, and stochastic events. Here, we review advances in epigenetic studies of discordant MZ twins, focusing on disease. The study of epigenetics and disease using discordant MZ twins offers the opportunity to control for many potential confounders encountered in general population studies, such as differences in genetic background, early-life environmental exposure, age, gender, and cohort effects. Recently, analysis of disease-discordant MZ twins has been successfully used to study epigenetic mechanisms in aging, cancer, autoimmune disease, psychiatric, neurological, and multiple other traits. Epigenetic aberrations have been found in a range of phenotypes, and challenges have been identified, including sampling time, tissue specificity, validation, and replication. The results have relevance for personalized medicine approaches, including the identification of prognostic, diagnostic, and therapeutic targets. The findings also help to identify epigenetic markers of environmental risk and molecular mechanisms involved in disease and disease progression, which have implications both for understanding disease and for future medical research.

Figure 1

Shared and non-shared potential epigenetic confounding factors throughout the lifetime of MZ twins and unrelated individuals. MZ twins, in contrast with unrelated individuals, share most genetic variants, as well as similar prenatal and early-life environments. The in utero environment is also shared by MZ twins, although to different degrees: they can have a shared placenta and amnion (monochorionic monoamniotic, left picture), a shared placenta but different amnion (monochorionic diamniotic, middle), or a different placenta and amnion (dichorionic diamniotic, right). Epigenetic studies using MZ twins allow the control of most genetic, maternal, environmental, and cohort effects.

Figure 2

Heritable and environmental factors contributing to disease. For each complex disease we show the fraction of the phenotypic variance explained by heritable factors, shared environmental factors, and non-shared environmental factors. The estimates were obtained from published studies of stomach, colorectum, pancreas, lung, breast, cervical, uterine, ovary, prostate, bladder and leukemia cancers [29]; strict autism [27]; psoriasis [56]; myocardial infarction [57]; gestational diabetes, type 1 diabetes, and type 2 diabetes [25].