Neuroepigenetics of Schizophrenia

Abstract

Schizophrenia is a complex disorder of the brain, where genetic variants explain only a portion of risk. Neuroepigenetic mechanisms may explain the remaining share of risk, as well as the transition from susceptibility to the actual disease. Here, we discuss the most recent findings in the field of brain epigenetics applied to the study of schizophrenia. Methylome studies have found several candidates exhibiting methylation modifications in association with the disorder, but genes affected do not always overlap. Notably, these studies converge in that genes within the schizophrenia risk loci or genes differentially methylated in patients affected with the disorder are dynamically regulated during early life. They also imply that schizophrenia-associated genetic variation may affect DNA methylation in fetal and adult brains. Histone modifications may help mediating the effect of genetic risk variants associated with schizophrenia, and regulating chromatin higher-order structure. The 3D-organization of chromatin in the brain creates physical interactions within chromosomes, so that schizophrenia-associated genetic variants can be linked with genes distant from their loci; this suggests that chromatin conformation matters in the mechanism of risk for the disorder. Non-coding RNAs provide a novel and complex mechanism of gene regulation potentially significant for schizophrenia, as proposed by research on specific microRNAs and long non-coding RNAs (lncRNAs). Finally, a recent study in epitranscriptomics identifies RNA methylation as a further epigenetic mechanism active in human brain and specifically in a portion of the transcriptome associated with schizophrenia susceptibility. These findings indicate that, as expected from the complexity of the brain and its development, several epigenetic mechanisms may intervene in the etiopathogenesis of schizophrenia. An understanding of their roles calls for research approaches integrating the investigation of different epigenetic mechanisms and of environmental and genetic risk, in the context of development.

Keywords: Chromatin organization; DNA methylation; Development; Epigenetics; Epitranscriptomics; Histone modifications; Non-coding RNAs; Schizophrenia.