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.
Highlights
Background for Environmental Impacts on theMCH System and Findings Relevant to PsychosisThe melanotropins are a family of peptides profoundly responsive to cues from the physical environment, originally investigated in fish for their pronounced effects on pigment dispersion in response to changes in background light levels [25–27], with the peptide alpha-melanocyte-stimulating hormone increasing pigment dispersion and melanin-concentrating hormone peptide (MCH) diminishing dispersion
1st exon CpG site is hypomethylated in psychosis evidence that methylation may control alternative splicing smoking hypermethylates a CpG site in the 50 UTR region; predicted to affect expression of the 353aa MCHR1 protein reported by NCBI; hypermethylation in the promoter region may decrease expression of the 353aa protein and/or the alternative 422aa protein
In studies investigating the sensory gating traits seen in psychosis, the administration of the psychoactive ingredient of cannabis (THC) to rats disrupts auditory gating in a manner consistent with what is seen in individuals with schizophrenia [90], confirming prior work that administering THC or other cannabinoid receptor agonists to rodents disrupts auditory gating [91,92]
Summary
The realization that chronic psychotic disorders might be controlled by environmental factors was made clear long ago when studies of identical twins revealed a discordance rate for schizophrenia of ~50% [1]. In an environment that promotes consistent epigenetic methylation of a gene, the end result can be the loss of methylation capability at that site, which should be maladaptive given the existing environment that encouraged it in the first place The explanation for this apparent conflict may lie in the enzymatic reversal of methylation which involve conversion of 5mC to 5-hydroxy-methyl-cytosine (5hmC) as the first step, followed by oxidation intermediates and base excision repair [15]. Most studies of methylation have not discriminated between 5mC and 5hmC, which has bearing on all of the current research to be reviewed here and is potentially problematic for CpG sites in the gene body but not quite as serious an oversight for the promoter region and the first exon, where the functional outcome is quite similar in terms of expression of the gene. The many SNPs known to exist at the CpG sites reviewed in this manuscript are too rare to be of relevance to psychosis
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