Monozygotic Twins Exhibit Numerous Epigenetic Differences: Clues to Twin Discordance?

Abstract

The goal of this pilot study was to explore the putative molecular mechanisms underlying the phenotypic discordance of monozygotic (MZ) twins. Thus, patterns of epigenetic DNA modification were investigated in the 5'-regulatory region of the dopamine D2 receptor gene (DRD2) in two pairs of monozygotic twins, one concordant and one discordant for schizophrenia. The bisulfite DNA modification-based approach was used to fine-map methylated cytosines in DRD2 in genomic DNA extracted from lymphocytes. Numerous DNA methylation differences were identified in the analyzed region both within and between the pairs of MZ twins. "Epigenetic distances" between MZ twins were calculated and used for the comparison of twin DRD2 methylation profiles. It was detected that the affected twin from the pair discordant for schizophrenia was epigenetically "closer" to the affected concordant twins than to his unaffected MZ co-twin. Although the epigenetic analysis was conducted for only several hundred base pairs of DRD2, the fact that numerous studies identified nonuniform methylation patterns across the clones of bisulfite-modified DNA from the same individual, as well as nonuniform patterns across different individuals, argues for the universality of intra- and interindividual epigenetic variation. Epigenetic studies should provide insight into the molecular causes of differential susceptibility to a disease in genetically identical organisms that may generalize to singletons.

Discovering Endophenotypes for Major Depression

“…For example, environmental events (for example, early childhood stressors) correlate with the development of psychiatric disorders in adults (Heim and Nemeroff, 2001). Indeed, as witnessed by multiple studies of discordant monozygotic twins where one has the disorder and the other does not, epigenetic mechanisms must be operative to control behavior in genetically identical populations (Petronis et al, 2003). A critical question involves the mechanism by which early life events regulate long-term changes in behavior and sustained differences in gene expression.…”

Genetic or epigenetic difference causing discordance between monozygotic twins as a clue to molecular basis of mental disorders

“…They analyzed the DNA samples obtained from two pairs of twins discordant or concordant for schizophrenia and examined the DNA methylation status of the upstream region of the dopamine D2 receptor. 9 They examined the difference of the DNA methylation status between twins, which was named 'epigenetic distance'. They reported that epigenetic difference was larger between discordant twins compared with concordant twins.…”

“…[6][7][8][9][10] These studies seem to have induced a paradigm shift to the third-generation twin research, from focusing on the higher concordance rate in MZ twins, to looking for the genetic or epigenetic difference between MZ discordant twins. 11 In this review, the theoretical concept of such study to search for genetic or epigenetic difference between MZ discordant twins is explained and its application to schizophrenia and bipolar disorder is summarized.…”

Expression profiling in monozygotic twins discordant for bipolar disorder reveals dysregulation of the WNT signalling pathway

“…Epigenetic factors are a more commonly detected source of variation between MZ twins and are an attractive mechanism for the observed phenotypic differences. 15,16 The role of epigenetic regulation of gene expression in complex diseases, including psychiatric disorders is attracting increasing molecular and epidemiological support. 17 The use of twins also increases capacity over population-based studies to conduct multivariate analyses to decipher complex relationships between genes and pleiotropic effects.…”