Methylation markers in a cohort of first-episode psychosis patients treated with risperidone

The first-episode psychosis (FEP) is a critical stage of schizophrenia, a severe and multifactorial psychiatric disorder. This study aimed to identify DNA methylation markers in blood related to both: treatment with risperidone and markers related to response status (responder x non-responder) in an antipsychotic-naïve FEP cohort before (anFEP) and after risperidone treatment (FEP-2M). A total of 251 subjects were analyzed: 125 FEP individuals and 126 health controls (HC). We used the HumanIllumina450K and the EPIC arrays to identify differentially methylated positions (DMPs) or regions (DMRs) and considered smoking and cell-type proportions as covariates. Differences in estimated blood cell type proportions were identified comparing anFEP and HC or anFEP and FEP-2M, with anFEP presenting abnormal proportions. DNA methylation estimated smoking status was also different between FEP and HC, with cases presenting higher scores, as expected. We detected 4 DMPs (in KAZN, UOX, COL11A2 and IL1A genes) and 1 DMR (in IL1A) comparing anFEP and FEP-2M, with three CpGs being also differentially methylated comparing anFEP and HC. Differentially methylated CpGs in KAZN, COL11A2 and IL1A genes were previously found in schizophrenia brain and blood tissues. Considering response to treatment based on Positive and Negative Syndrome Scale (PANSS), 100 DMPs and 291 DMRs, lying in 249 genes, were identified in association with any PANSS domain. They were enriched for cell adhesion and calcium ion binding categories, and 22 were associated with schizophrenia in the last genome-wide association study. Among our findings, the most replicated genes in other epigenome-wide association studies (e.g. KAZN, PRDM16, PRKCZ, RERE, SKI, PEX10 and PINK1) are located in chromosome 1p36 and were differentially methylated in relation to negative symptoms of schizophrenia. Our longitudinal study revealed novel genes that may be regulated by risperidone and could be used as response markers to improve prognosis. Some of them have been previously associated to the disorder, environmental risk factors and antipsychotic response and side effects, indicating the importance of longitudinal methylation study in blood of antipsychotic-naive FEP to identify novel and known biological markers for treatment of schizophrenia.