Methylation as an epigenetic source of random genetic effects in the classical twin design

Abstract

The epigenetic effects of cytosine methylation on gene expression are an acknowledged source of phenotypic variance. The discordant monozygotic (MZ) twin design has been used to demonstrate the role of methylation in disease. Application of the classical twin design, featuring both monozygotic and dizygotic twins, has demonstrated that individual differences in methylation levels are attributable to genetic and environmental (including stochastic) factors, with the latter explaining most of the variance. What implications epigenetic sources of variance have for the twin modeling of (non-epigenetic) phenotypes such as height and IQ is an open question. One possibility is that epigenetic effects are absorbed by the variance component attributable to unshared environmental. Another possibility is that such effects form an independent source of variance distinguishable in principle from standard genetic and environmental sources. In the present paper, we conceptualized epigenetic processes as giving rise to randomness in the effects of polygenetic influences. This means that the regression coefficient in the regression of the phenotype on the polygenic factor, as specified in the twin model, varies over individuals. We investigate the consequences of ignoring this randomness in the standard twin model.