Schizophrenia is a complex disorder involving both genetic and environmental factors. Epigenetic is a growing theory to explain these interactions at a molecular level. It is well-known that schizophrenia begins with prodromal symptoms and patients undergoing subthreshold symptoms are named ultra-high risk (UHR) subjects. Therapeutic and prognostic attitude remain challenging for this population. According to the model of the gene-environment interactions, the psychotic transition in adolescence could be related to epigenetic changes during the psychotic transition.

We designed and performed the first longitudinal study about whole-genome DNA methylation changes. Thirty-nine UHR patients were recruited in specialized center C’JAAD - Centre Hospitalier Ste Anne - Paris (France). During follow-up, 14 of them became psychotic (converters) according to the validated scale CAARMS. Initial and final methylation were investigated by Infinium Human Methylation450 BeadChip for 450,000 CpG after bisulfite conversion.

The psychotic transition was not associated with global methylation changes. Linear models failed to identify CpG and genes significantly associated with psychotic transition after Bonferroni correction. Analyses of the top results provided a cluster, which could classify perfectly converters and non-converters. These genes of interest are over-represented in biological pathways with relevance for psychotic physiopathology. Individual analyses highlighted the biological heterogeneity of the psychotic transition.

Improving physiopathological understanding of psychotic transition is a current challenge to identify biomarkers and to develop targeted preventive interventions available in clinical practice for UHR subjects. The epigenetic processes and in particular DNA methylation could be interesting factors.