Epigenetic Mechanisms in Schizophrenia: A Review of Evidence from the Past Five Years

Abstract

Schizophrenia is a highly heritable yet polygenic and clinically heterogeneous psychiatric disorder for which DNA sequence variation alone does not fully explain individual risk, age of onset, or treatment response. Over the past five years, epigenome-wide association studies, chromatin profiling, and non-coding RNA analyses have provided convergent evidence that DNA methylation, histone modification, and regulatory RNAs mediate the interaction between genetic vulnerability and environmental exposure across the lifespan. This narrative review synthesizes literature published between 2021 and 2026 on three major epigenetic mechanisms implicated in schizophrenia: DNA methylation dysregulation, histone post-translational modification, and dysregulated non-coding RNA networks, together with emerging evidence on prenatal and childhood adversity as upstream triggers and antipsychotic medication, particularly clozapine, as both a downstream confound and a potential epigenetic modulator. Differentially methylated positions identified through recent epigenome-wide association studies converge with risk loci identified by large genome-wide association studies, histone acetylation and methylation are altered in postmortem cortical tissue and oligodendroglial-lineage cells, and long non-coding RNAs such as GOMAFU together with several microRNAs are dysregulated in blood and brain. Epigenetic clocks and methylation risk scores show promise as peripheral biomarkers, yet tissue specificity, medication confounding, and a scarcity of longitudinal data remain major barriers to clinical translation. Continued integration of multi-omic and longitudinal study designs is required before epigenetic markers can be translated into tools for early detection, patient stratification, or treatment monitoring in schizophrenia.