The Epigenetics of Psychosis: A Structured Review with Representative Loci

Abstract

The evidence for an environmental component in chronic psychotic disorders is strong and research on the epigenetic manifestations of these environmental impacts has commenced in earnest. In reviewing this research, the focus is on three genes as models for differential methylation, MCHR1, AKT1 and TDO2, each of which have been investigated for genetic association with psychotic disorders. Environmental factors associated with psychotic disorders, and which interact with these model genes, are explored in depth. The location of transcription factor motifs relative to key methylation sites is evaluated for predicted gene expression results, and for other sites, evidence is presented for methylation directing alternative splicing. Experimental results from key studies show differential methylation: for MCHR1, in psychosis cases versus controls; for AKT1, as a pre-existing methylation pattern influencing brain activation following acute administration of a psychosis-eliciting environmental stimulus; and for TDO2, in a pattern associated with a developmental factor of risk for psychosis, in all cases the predicted expression impact being highly dependent on location. Methylation induced by smoking, a confounding variable, exhibits an intriguing pattern for all three genes. Finally, how differential methylation meshes with Darwinian principles is examined, in particular as it relates to the “flexible stem” theory of evolution.

Two Genetic Mechanisms in Two Siblings with Intellectual Disability, Autism Spectrum Disorder, and Psychosis

“…Tdo2 -knockout mice showed anxiolytic behaviors, increased adult neurogenesis [ 50 ], and enhanced exploratory behavior and cognitive function [ 51 ]. The TDO2 protein was also reported as a mediator of environmental factors associated with psychosis through epigenetic mechanisms [ 52 ].…”

Diverse avenues of research support the transmethylation theory of psychosis: implications for neuroprotection

“…The biochemical cycling of methyl groups thought to relate to psychosis was one such area of endeavor. Termed the transmethylation hypothesis, the origins of this theory can be traced to the historical observation that many drugs capable of causing psychosis contained methylated amino groups, as reviewed by Grayson et al [1]. The formation of tertiary amines is of particular interest, as will be made clear in a subsequent section.…”