Keynote Speaker: Dr. Art Petronis University of Toronto, Pharmacology and Toxicology, Canada Epigenomics of major psychosis The traditional aetiological approach to understanding the causes of psychiatric disorders has focussed on the interplay between genetic and environmental factors. There are, however, numerous epidemiological, clinical, and molecular peculiarities associated with complex psychiatric phenotypes that are hard to explain using traditional gene- and environment-based approaches. For example, the non-Mendelian mode of inheritance, discordance between monozygotic twins, late age of onset, sexual dimorphism, parental-origin effects, and significant fluctuation of the disease course suggest that epigenetic factors may also play a role in disease aetiology. Genomic DNA was extracted from frontal cortex of 105 brains from individuals affected with schizophrenia and bipolar disorder along with matched controls (the Stanley Brain Bank). The unmethylated fraction of genomic DNA was enriched using methylation-sensitive restriction enzymes and adaptor-ligation PCR. Following enrichment, samples were labelled and hybridized on CpG island microarrays to interrogate 12,000 regulatory sequences across the genome. Significant regions were verified using the sodium bisulfite fine-mapping of methylated cytosines and pyrosequencing. ~0.3% of loci exhibited statistically significant (after correction for multiple testing) DNA methylation differences between the affected individuals and controls. The identified DNA methylation changes fall into three categories: i) regions that are hypo- or hyper-methylated in affected conditions; ii) regions showing increased epigenetic variability in psychiatric patients; iii) regions where a subsection of psychiatric patients show a highly-skewed methylation profile at specific CpG sites. Evidence for psychosis-associated DNA methylation differences was detected in the loci involved in glutamatergic and GABAergic neurotransmission, brain development, and other processes functionally-linked to disease etiology. DNA methylation changes in a significant proportion of these loci correspond to reported changes of steady-state mRNA level associated with psychosis. Gene ontology analysis highlighted epigenetic disruption to loci involved in mitochondrial function, brain development, and stress response. Methylome network analysis uncovered decreased epigenetic modularity in the affected individuals, suggesting that systemic epigenetic dysfunction may be associated with major psychosis. This first epigenome scan in major psychosis demonstrated that epigenetic changes do exist in major psychosis and such can be detected using the microarray-based screening technologies. In terms of further activities, much larger scale epigenome studies in psychiatric disease are warranted. In addition to the brain, tissues that are not directly affected by the disease should also be investigated. This effort may allow for differentiation between causal and non-causal epigenetic changes.