Dempster EL, Pidsley R, Schalkwyk LC, Owens S, Georgiades A, Kane F, Kalidindi S, Picchioni M, Kravariti E, Toulopoulou T, Murray RM, Mill J.
Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. Hum Mol Genet.
2011 Dec 15
Comments on News and Primary Papers
Comment by: Schahram Akbarian
Submitted 7 October 2011
Posted 7 October 2011
The genetic risk architecture is still very difficult to "capture" for a large majority of patients diagnosed with schizophrenia or related diseases. Therefore, studies like that of Dempster et al., who profiled DNA methylation (a type of "epigenetic" modification of cytosine that residues mostly at sites of CpG dinucleotides in the genome) in blood cells of monozygotic twins discordant for schizophrenia, provide an important additional layer of information. The idea is that the disease process in the affected twin leaves behind a molecular signature (in the study by Dempster et al., this would be a change in DNA methylation) that is not found in the healthy twin, with the implication that this signal is related to disease etiology or disease process and treatment, etc.
Dempster and colleagues screened approximately 20 twin pairs. I believe the Illumina bead system they used probes primarily annotated promoters; on a genomewide level, they found, overall, quite subtle changes. One of the more prominent findings is hypomethylation of one specific CpG dinucleotide associated with ST6GALNAC1, a gene regulating protein glycosylation, with additional changes in a dozen or so genes. Hypomethylation of ST6GALNAC1 (which the authors further verified in postmortem brains of subjects with schizophrenia) at sequences proximal to promoters is generally associated with increased expression, but it is not clear if this is the case in the twin blood or the postmortem brain. Interestingly, as the authors point out, the same gene (ST6GALNAC1) may harbor an excess copy in some subjects on the psychosis spectrum. This is a good example of the possibility that some of the genes that are potentially linked to psychosis because of DNA sequence and copy number changes may also show up in epigenetic studies such as that of Dempster and colleagues. Whether a genetic variation or mutation somewhere else in the genome "drives" the epigenetic changes at ST6GALNAC1 and other genes is, of course, hard to prove.
The most important challenge to the epigenetics and psychosis fields is, at least in my opinion, that of reproducibility and independent replication. In other words, will we be able to replicate, in independent studies, epigenetic alterations in blood or postmortem brain tissue, reported to be "highly significant" for cohorts comprising a few dozen or fewer cases? With fewer than five published studies (to the best of my knowledge) that measured DNA methylation on a genomewide scale in mood and psychosis spectrum disorders, it is still hard to predict whether DNA and histone modification mapping will provide valuable clues to the underlying neurobiology of disease. I take an optimistic view, and would like to predict that DNA methylation and histone modification mapping will provide a very important additional layer of information when paired with whole-genome sequencing and transcriptome (RNA expression) profiling.
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