Between 20% and 30% of patients with schizophrenia (SCZ)—and up to 50% patients with SCZ older than 50—develop tardive dyskinesia (TD), according to a study published in Genes & Genomics. To better understand this association, Ping Zhang and colleagues examined if DNA methylation factors heavily in the development of TD.
They conducted a genome-wide DNA methylation analysis by using methylated DNA immunoprecipitation together with next-generation sequencing (MeDIP-Seq) in patients with SCZ with TD and in those without TD (NTD) and compared results to those of healthy participants matched for age, sex, and education.
In an independent sample, the study team used pyrosequencing, considered the gold standard for data analysis in epigenetic studies, to quantify DNA methylation levels of several methylated genes for validation.
Through the use of genome-wide MeDIP-Seq analysis, the study team found 116 genes that were significantly differentially methylated in promotor regions, when comparing the TD group with the NTD group. This included 50 hypomethylated genes (top four genes: DERL3, GSTA4, KNCN, and LRRK1) and 66 hypermethylated genes (top four genes: GABRR1, VANGL2, ZNF534, and ZNF746).
Study Relied on Peripheral Blood Versus Brain Tissue
Earlier reports showed some of these genes (such as DERL3, DLGAP2, GABRR1, KLRG2, LRRK1, VANGL2, and ZP3) were correlated with methylation in SCZ. Several pathways were identified as Gene Ontology (GO) enrichment and KEGG PATHWAY analyses. Through pyrosequencing, researchers confirmed the methylation of three genes (ARMC6, WDR75, and ZP3) in SCZ with TD to date.
The study authors acknowledge limitations in their research. In addition to the small sample sizes in the genome-wide methylation and conformation studies, WDR75 and ZP3 genes had higher significance linked with TD (P=1.63–05 and 3.82–06, respectively) in the genome-wide DNA methylation study. In the validation study, however, the correlations of WDR75 and ZP3 genes in TD compared with the NTD are not significant (P=0.0246 and 0.0599, respectively). Furthermore, collecting brain tissue for the study of central nervous system diseases presents a challenge. This study therefore relied on peripheral blood versus brain tissue.
“We identified [a] number of methylation genes and pathways for TD and confirmed the results for several genes; therefore, this study provides potential biomarkers of earlier therapeutic interventions to reduce the impact of [SCZ] with TD,” the study authors wrote. These findings, they added, offer evidence of DNA promotor methylation status involved in SCZ with TD using MeDIP-Seq. Furthermore, by identifying a number of methylated genes and pathways for TD, the results point to potential biomarkers that can also act as a resource for replication in other populations.
Source: Adapted from: Zhang P, et al. Genes Genomics. 2023;45(10):1317.
