Meta-analysis of expression and methylation signatures indicates a stress-related epigenetic mechanism in multiple neuropsychiatric disorders

Similar environmental risk factors have been implicated in different neuropsychiatric disorders (including major psychiatric and neurodegenerative diseases), indicating the existence of common epigenetic mechanisms underlying the pathogenesis shared by different illnesses. To investigate such commonality, we applied an unsupervised computational approach identifying several consensus co-expression and co-methylation signatures from a data cohort of postmortem prefrontal cortex (PFC) samples from individuals with six different neuropsychiatric disorders—schizophrenia, bipolar disorder, major depression, alcoholism, Alzheimer’s and Parkinson’s—as well as healthy controls. Among our results, we identified a pair of strongly interrelated co-expression and co-methylation (E–M) signatures showing consistent and significant disease association in multiple types of disorders. This E–M signature was enriched for interneuron markers, and we further demonstrated that it is unlikely for this enrichment to be due to varying subpopulation abundance of normal interneurons across samples. Moreover, gene set enrichment analysis revealed overrepresentation of stress-related biological processes in this E–M signature. Our integrative analysis of expression and methylation profiles, therefore, suggests a stress-related epigenetic mechanism in the brain, which could be associated with the pathogenesis of multiple neuropsychiatric diseases.