SA90 - LONGITUDINAL EPIGENETIC CHANGES DURING THE ONSET OF PSYCHOSIS

Abstract

Background In the last 20 years, researchers and psychiatrists in the field of psychosis have moved from a conception of a chronic presentation to a more dynamic paradigm. Accordingly, psychotic disorders may progress from an at-risk presentation with subtle and non-specific symptoms to a chronic psychosis. The biological processes that underlie this progression remain largely unknown. Genetic and environmental factors are both necessary but insufficient to explain the emergence of psychosis in the at-risk individuals. Current pathophysiological hypotheses favor the gene x environment interactions that could be mediated by epigenetics. We have recently reported in Molecular Psychiatry the DNA methylation changes occurring during the onset of psychosis in genes involved in redox metabolism and axon guidance. We have completed this study by a functional analysis and have conducted the first longitudinal transcriptomic analysis in blood samples before and after the emergence of psychosis. Methods The transcriptomic analysis was conducted on peripheral blood samples from 31 at-risk individuals for psychosis who later convert to psychosis (converters) and 63 controls (non-converters) recruited in Ste Anne Hospital (Paris, France). Individuals were followed for one year and blood samples were collected at baseline and at the end of the follow-up. The design corresponds to an interaction between Group and Time, with individuals as their own controls. Differentially expressed gene between the two groups were identified by RNA sequencing on an initial discovery sub-group (n=15 individuals; 30 samples) using two different algorithms (edgeR and DESeq). Only concordant results from both algorithms were retained for further analyses, after correction for cell heterogeneity. The most promising results were replicated by high-throughput real-time qPCR in the whole cohort (n=94 individuals; 188 samples). We also explored the expression of 5 candidate genes from the previous methylomic study. Results From the RNAseq analyses, we identified 4 brain-expressed genes with significant longitudinal changes in converters compared to non-converters. One of these genes (CPT1A) was replicated in the larger cohort. CPT1A is involved in the fatty-acid metabolism, and represents a plausible target for the prevention of the onset of psychosis. Two candidate genes (NRP1 - axon guidance - and GSTM5 - redox metabolism) from the methylomic study were also confirmed. As expected, the observed hypermethylation during the onset of psychosis was correlated with a decrease of gene expression. Post-hoc analyses demonstrate that these results are unlikely to be due to psychotropic treatment modifications. Discussion This study sheds light on the epigenetic mechanisms that could explain the emergence of psychosis in adolescence. The results open new perspectives towards new phase-specific and disease-modifying therapeutic strategies for the prevention of psychosis. While peripheral investigations in psychiatric disease contain several limits, even in an intra-subject design, they could help to identify peripheral staging biomarkers for clinical practice. We will also discuss the importance of an integrative approach in the omics field.