Impacts of Polyenvironmental Factors on DNA Methylation in Patients With Psychosis

Only a few studies have investigated the association of environmental factors with DNA methylation in schizophrenia (SZ). Our study sought to investigate differentially methylated positions (DMPs) and differentially methylated regions (DMRs) between patients with psychosis and healthy controls (HCs) and to explore associations of aberrant methylation levels with the Korea-polyenvironmental risk score-I (K-PERS-I), a comprehensive tool measuring polyenvironmental risk factors for psychosis. Study Design: Blood-based methylome-wide association study (MWAS) was conducted in patients with psychosis (n = 414) and HCs (n = 225). For MWAS, a new cuttingedge technique, Methyl-Seq was employed. Using the KPERS-I, polyenvironmental risk factors were assessed. Psychosis-associated DMPs and DMRs were identified via beta-binomial regression, and their associations with K-PERS-I scores were examined. Study Results: We identified 1138 DMPs and 1611 DMRs associated with psychosis. In the correlation analysis, 12 DMPs-annotated genes and 11 DMRs-annotated genes were associated with childhood adversity. These genes were mainly implicated in neuronal development, neurotransmitter release, synaptic plasticity, immune response, and oxidative stress. For obstetric complications, most of top five DMPs-annotated genes were implicated in placenta function, embryonic development or gestation. For recent adult life events, top five DMPs- and DMRs-annotated genes were related to neurotransmitter production/release, oxidative stress, and stress regulation. Conclusions: We identified new psychosis-associated DMPs and DMRs. More importantly, we demonstrated how environmental factors can be biologically embedded in DNA methylation of certain genes in patients with psychosis. Ultimately, establishing causal pathways between these risk factors and DNA methylation could lead to the discovery of novel therapeutic targets.