Differential Methylation of the X-Chromosome is a Possible Source of Discordance for Bipolar Disorder Female Monozygotic Twins - Araceli Rosa et. al.

Monozygotic twins are twins arising from the same fertilized ovum, and therefore share the same genetic material. Thus, it is expected that they show similar patterns of gene expression. However, studies have shown that variations arise due to epigenetic modifications and might result in differential genetic expression among monozygotic twins. Some of these modifications include methylation of cytosines and histone modification. These modifications could influence the difference in susceptibility between identical twins to diseases such as bipolar disorder and schizophrenia. One such important modification is the chromosome X inactivation. This is highly likely to create a differential expression pattern since during the early stages of development; each of the cells in the female embryo randomly inactivates one X chromosome marked by hyper-methylation of CpG islands early in development, to achieve dosage compensation. This pattern has already been observed in X-linked single gene disorders. The objective of the study was to find out whether this had any linkage in bi-polar disorder (BD) and schizophrenia (SZ) gene expression discordance. DNA was collected from a total of 63 twin pairs, and a PCR targeting the CpG site and a highly polymeric Single Sequence Repeat (SSR) at the human androgen receptor was done, to determine the activation status of the X-chromosome. These samples were either concordant or discordant for BD and SZ. On analysis of these samples, only two pairs of DNA were found to be homozygous for the repeat polymorphism of which one was control and another discordant schizophrenia pair. The study also suggests that pairs of twins discordant for bi-polar disorder may be more discordant for X-linked inactivation patterns, which means that it may be more pronounced in the disorder. This was less pronounced in the schizophrenia pairs of DNA. Also, huge differences were found in the methylation of the maternal and paternal X alleles than concordant twin pairs in the discordant female bi-polar twins. These suggest that the difference in the level of X-chromosome inactivation may contribute to the difference in gene expression levels found in bi-polar disorder in the female monozygotes. Further study in this area, could be done with a larger sample size of monozygotic DNA twin samples with bi-polar disorder and schizophrenia to have a conclusive result.

Prahatha Venkatraman