GENOME-WIDE DNA METHYLATION ANALYSIS IN A LONGITUDINAL COHORT OF ANTIPSYCHOTIC-NAIVE FIRST EPISODE OF PSYCHOSIS PATIENTS

The study of the early stages of schizophrenia, the First-Episode Psychosis (FEP), is critical given that brain abnormalities and cognitive deficits are already present. Although less investigated than chronic schizophrenia, FEP individuals have a shorter period of medication and duration of symptoms. In this study, we aimed to identify genetic markers, using whole DNA methylation, for psychotic disorder and antipsychotic treatment in blood of a FEP cohort before and after two months of risperidone. Sixty controls and sixty antipsychotic naïve FEP patients followed-up for two months after risperidone (FEP-2M) were recruited. All patients were 16–40 years old and have met the criteria of psychotic diagnoses according to DSM-IV. We generated the DNA methylation data using the Human Illumina 450 K BeadChip microarray. We used limma R package, using two separate analyses: FEP x HC and FEPxFEP-2M (paired); and addind sex, age, smoking data and cell type proportion as covariates. We considered as significant Differentially Methylated Positions (DMPs) with p value lower than 0.05 after a Bonferroni correction for multiple comparisons and differentially methylated regions (DMRs) with at least two significant DMPs (FDR) within a 500 bp region. We found 5 DMRs and 16 DMPs comparing controls and FEP, and 14 DMRs and 77 DMPs between FEP before and after treatment. To our knowledge, this is the first study to find DMRs in a longitudinal cohort of antipsychotic naïve FEP patients. Collectively, DMRs in the longitudinal comparison seem to be related to the adverse effects and the response to risperidone. Notably, the most associated genomic region in schizophrenia (previously reported by the PGC), the MHC region, is differentially methylated in patients after the treatment, demonstrating an epigenetic modification caused by risperidone in an important schizophrenia genomic region. Identifying the genetic and molecular changes of drug response is one of the first steps through personalized medicine, further studies should replicate these results and aim antipsychotic naive individuals treated with other antipsychotics.