Psychotic symptoms associated increased CpG methylation of metabotropic glutamate receptor 8 gene in Chinese Han males with schizophrenia and methamphetamine induced psychotic disorder: a longitudinal study

Abstract

Methamphetamine use can produce psychotic symptoms almost indistinguishable from schizophrenia (SCZ). Variation in DNA methylation may be closely implicated in the etiology and longitudinal development of psychiatric disorders. However, the relationship between psychotic symptoms, functional disability, and DNA methylation is still unclear. This study consists of three periods: discovery, validation, and follow-up. In the discovery stage, we employed genome-wide DNA methylation profiling (Illumina 450K) in peripheral blood mononuclear cells to test whether DNA methylation associates with psychotic symptoms and function state in representative SCZ and methamphetamine-induced psychotic disorder (MIP) patients. Then, we found seven differentially methylated regions/genes (DMRs, in UBA6, APOL3, KIF17, MLLT3, GRM8, CSNK1E, SETDB1) overlapping with genetic variants reported in previous studies of psychosis. In the validation stage, we compared the above-mentioned seven genes by MethLight qPCR method in Chinese Han males (N = 109 SCZ patients, N = 99 methamphetamine use disorder with MIP patients, N = 150 methamphetamine use disorder without MIP patients, N = 282 normal controls, age range: 18–50 years). GRM8 showed robustly altered methylation, which has passed rigorous filtration in subsequent validation, suggesting a remarkable contribution to SCZ and MIP. In addition, hypermethylation of GRM8 showed a significant association with the total scores of the Positive Negative Syndrome Scale and WHO disability assessment schedule II in both baseline and follow-up periods. Our findings suggest that increased CpG methylation in the promoter of GRM8 is a potential candidate epigenetic biomarker of psychotic symptoms in transdiagnostic samples of SCZ and MIP.