Differential methylation of the X‐chromosome is a possible source of discordance for bipolar disorder female monozygotic twins

Abstract

Monozygotic (MZ) twins may be subject to epigenetic modifications that could result in different patterns of gene expression. Several lines of evidence suggest that epigenetic factors may underlie mental disorders such as bipolar disorder (BD) and schizophrenia (SZ). One important epigenetic modification, of relevance to female MZ twins, is X-chromosome inactivation. Some MZ female twin pairs are discordant for monogenic X linked disorders because of differential X inactivation. We postulated that similar mechanisms may also occur in disorders with more complex inheritance including BD and SZ. Examination of X-chromosome inactivation patterns in DNA samples from blood and/or buccal swabs in a series of 63 female MZ twin pairs concordant or discordant for BD or SZ and healthy MZ controls suggests a potential contribution from X-linked loci to discordance within twin pairs for BD but is inconclusive for SZ. Discordant female bipolar twins showed greater differences in the methylation of the maternal and paternal X alleles than concordant twin pairs and suggest that differential skewing of X-chromosome inactivation may contribute to the discordance observed for bipolar disorder in female MZ twin pairs and the potential involvement of X-linked loci in the disorder.

Not really identical: Epigenetic differences in monozygotic twins and implications for twin studies in psychiatry

“…They found a large degree of MZ co-twin DNA methylation variation in all the tissue samples investigated, validating their findings using sodium bisulfite modification based mapping of methylated cytosines in CpG islands [Frommer et al, 1992;Kaminsky et al, 2009]. There are a number of specific epigenetic mechanisms that may alter phenotype, including skewed X-inactivation in FMZ twins, imprinting (differential expression of genes inherited from the mother or father), and DNA methylation, that are discussed below [Gringras and Chen, 2001;Boomsma et al, 2002;Rosa et al, 2008].…”

“…Comparing concordance rates between FMZ and male MZ (MMZ) twin pairs can potentially identify X-linked loci that influence the manifestation of disease states. If polymorphic X-linked loci are involved, FMZ pairs should be more discordant than MMZ due to skewed X-inactivation [Rosa et al, 2008]. This was observed by Loat et al [2004] in a study that tested a large sample of same-sex twin pairs on several social, behavioral, and cognitive measures: concordance rates were higher in almost all categories in MMZ twins than in FMZ twins.…”

“…One molecular mechanism that could be both a source of stochastic variation in gene expression and a mediator of environmental effects on phenotype is epigenetics. Epigenetic factors that may cause MZ twin pairs to diverge and account to a large degree for some of their phenotypic discordance include skewed X-inactivation in female MZ (FMZ) twins, imprinting, and other modifications of chromosomal DNA and gene expression, especially through DNA methylation [Gringras and Chen, 2001;Boomsma et al, 2002;Rosa et al, 2008].…”

“…Numerous studies have identified skewed X-inactivation in FMZ twin pairs discordant for X-linked medical conditions such as fragile X-syndrome [Kruyer et al, 1994], Duchenne muscular dystrophy [Zneimer et al, 1993], color blindness [Jørgensen et al, 1992], X-linked immunodeficiencies, LeschNyham disease, and hemophilia [Rosa et al, 2008]. Skewed X-inactivation can aid in the investigation of complex diseases, including the broad spectrum of psychiatric illnesses.…”

“…In schizophrenia, some evidence points to the possibility that the disease may be X-linked and thus modulated by skewed X-inactivation: An excess of X-chromosome aneuploidies (XXX and XXY) among patients has been found in a subgroup of familial cases [DeLisi et al, 1994;Rosa et al, 2008], and MZ twin concordance for psychosis is slightly higher in males than females [Rosa et al, 2008].…”