6 October 2011. DNA methylation changes in monozygotic twins discordant for schizophrenia and bipolar disorder provide strong evidence for a role of epigenetic alterations in psychosis, according to a new study published online September 22 in Human Molecular Genetics. In the first large-scale, genomewide analysis of epigenetic changes in twin pairs discordant for psychosis, Jonathan Mill and Robin Murray, of King’s College London, and colleagues report altered DNA methylation patterns associated with both schizophrenia and bipolar disorder.
The high heritability of psychotic disorders is widely recognized, although poorly understood (Craddock et al., 2005). The vast majority of studies have examined the role of genes in schizophrenia and bipolar disorder, although recently epigenetic alterations—mitotically heritable changes that control gene activity without altering the DNA sequence—have garnered attention in these illnesses (Pidsley and Mill, 2011: see also SRF Current Hypothesis paper by D. Grayson). Epigenetic changes are principally brought about through DNA methylation at cytosine-guanine dinucleotide (CpG) sites and chromatin alterations (Henikoff and Matzke, 1997).
Mill's group has previously reported DNA methylation changes in schizophrenia and bipolar disorder (see SRF related news story) in a large number of unrelated individuals. The study of monozygotic twins discordant for psychosis is a particularly powerful approach, since epigenetic changes can be measured independent of variation in genetic code (Bell and Spector, 2011). This approach has been used successfully outside the field (Javierre et al., 2010); however, similar studies of psychosis have been limited to small sample sizes of only a few twin pairs (Petronis et al., 2003; Kuratomi et al., 2008).
Using peripheral blood samples from 22 twin pairs (11 pairs each discordant for schizophrenia and bipolar disorder, respectively), first authors Emma Dempster and Ruth Pidsley performed a genomewide analysis of DNA methylation at CpG sites using microarray. A number of disease-associated changes were found, and a pathway analysis of top loci revealed that epigenetic changes were prominent in a number of networks related to psychiatric illness and neurodevelopment. Additionally, methylation alterations were also found at loci not previously implicated in either illness. Some DNA methylation differences were present across all twin pairs, while others appeared to be more rare (appearing in only a single pair or two), suggesting that certain epigenetic alterations in psychotic illness may be more widespread than others.
Interestingly, a number of epigenetic differences were found across a combined psychosis group, while others were specific to schizophrenia or bipolar disorder. When all pairs were pooled together into a psychosis group, resulting in the largest sample size, ST6GALNAC1, a gene involved in protein glycosylation, emerged as the most differentially methylated region. Hypomethylation of this CpG site was confirmed using postmortem brain samples from the Stanley Foundation Neuropathology Consortium. Given that hypomethylation typically leads to gene overexpression, the results of the current study are consistent with a duplication in ST6GALNAC1 that was recently implicated in schizophrenia (Xu et al., 2008; see SRF related news story).
When the twin pairs were broken down into schizophrenia and bipolar disorder groups, differences emerged. The top hit in schizophrenia twin pairs was a CpG site located upstream of the gene encoding pseudouridylate synthase 3 (PUS3), which was hypermethylated in affected twins. In contrast, in bipolar disorder twin pairs, the largest difference was a hypomethylation within a G protein-coupled receptor gene, GPR24, which has previously been implicated as a susceptibility gene for both schizophrenia and bipolar disorder (Severinsen et al., 2006). Of note, opposite methylation patterns were also found between the two illnesses at the same sites, such as the hypermethylation of the promoter of zinc finger gene ZNF659 in schizophrenia twins but hypomethylation in bipolar twins.
This study further implicates epigenetic alterations in the etiology of psychotic illness. Given the success of the current methodology in detecting alterations in methylation patterns, the authors note that “future efforts should focus on collecting biological material from additional twin pairs for use in methylomic analyses.”—Allison Curley.
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 Sep 22. Abstract