While they can’t see through lead or stop bullets with their chest, twins do have a superpower of their own – when it comes to unraveling the complex genomic and epigenomic changes underlying diseases and disorders. In their latest adventure monozygotic twins are helping to understand the DNA methylation changes associated with schizophrenia. The epigenomics of schizophrenia are complex, not only on their own, but because every patient has been exposed to antipsychotic medication, which can change DNA methylation more drastically than whatever causes the disease. This means uncovering the changes that are involved in the disease is much more complicated.

To overcome this limitation some clever experimental designs have been undertaken. First, we saw the tissue specific methylomics of olanzapine that highlighted how a common antipsychotic causes changes that previously were thought to be part of schizophrenia. Then we saw an approach that compared adult schizophrenic brains to developing brains, in order to tune out the noise, which characterized some the neurodevelopmental DNA methylation altered in schizophrenia.

DNA Methylation and Schizophrenia

Now, the lab of Shiva Singh at the University of Western Ontario (Canada) has dug deeper into the web of epigenetic inheritance (specifically intergenerational) by taking a genetical epigenomics approach. The researchers examined the DNA methylation of monozygotic twin pairs discordant for schizophrenia along with their parents, allowing the team to determine if the alterations were inherited or de novo.

The researchers analyzed these changes using MeDIP-chip promoter arrays on peripheral blood on two highly informative pedigrees. Here’s what they found:

Some de novo and inherited alterations to DNA methylation, as assessed by the identical twins parent’s methylomes, are present in the twin affected by schizophrenia and not the unaffected identical twin.

Most differentially methylated regions (DMRs) are de novo and unique to the pedigree, with a few ‘inherited’ (25% and 13% of DMRs in respective families).

There were 138 DMRs between twins in pair 1 and 330 in twin pair 2.

In order to tune out the noise of lifetime, they then only compared the epigenomic alterations in the affected twin that were shared in both diverse families. These DMRs belong to 27 genes, most of which appear to be inherited. Interestingly, these inherited DMRs tend to lie in imprinted genes and those related to chromatin architecture. SNORD 115/116 and histone clusters were the vast majority of these inherited DMRs. The other DMRs identified include PTPRN2, TTYH3, ZFP41, GNAS, and XIST and have previously been implicated in schizophrenia, neurodevelopment, and/or exposure to antipsychotics.



Altered and Inherited DNA Methylation

Interestingly, the SNORD 115 and 116 clusters on 15q11 produce numerous ncRNA species that are implicated in Prader Wili Syndrome, Angelman Syndrome, Psychosis, and 1-3% of Autism Spectrum Disorders. Previously, the Singh lab has shown that SNORD 115 and 116 can be environmentally altered in DNA methylation and transcription by examining multiple mouse models of prenatal alcohol exposure. A more recent study by an unrelated group also showed that the members of the SNORD 115 family were the top DMRs passed from the sperm of at risk autistic fathers to the brains of affected children.

Lead author Christina Castellani shares that “Schizophrenia, like other complex diseases, holds promise for helping to understand the complexity of epigenomes and their role in disease. Monozygotic twins allow for us to reduce the heterogeneity in studies of this kind by using nature’s best match to unravel important differences in those with disease presentation versus those who do not show symptoms. It is becoming increasingly apparent that we as researchers have only hit the tip of the iceberg with uncovering the complex architecture that lies in our genomes.”

Check out the complexities of brain inheritance in BMC Medical Genomics, May 2015