Epigenetic factors in the 22q11.2 deletion syndrome in relation to stress and schizophrenia

22q11.2 deletion syndrome (22q11.2DS) stands out as one of the most significant risk factors for schizophrenia (SCZ), with approximately 40% of individuals with 22q11.2DS experiencing psychosis. The presence of discordant phenotypes among monozygotic twins, along with the involvement of environmental factors in the multiple-hit model hypothesis for psychosis onset, underscores the potential role of epigenetic modifications in the development of neuropsychiatric disorders among individuals with 22q11.2DS. To gain a deeper understanding of the underlying biological mechanisms, we conducted a translational study using three datasets: a genome-wide methylation dataset from peripheral blood of individuals with 22q11.2DS with or without SCZ, a microRNA expression dataset from the same cohort, and a second genome-wide methylation dataset obtained from a mouse model exploring gene-environment interactions. Human recruitment was carried out at a specialized center focusing on rare psychiatric disorders and included one pair of monozygotic twins discordant for SCZ. In the animal model, DNA extraction was performed from the prefrontal cortex among four groups : wild-type and Df(h22q11)/+ mice, with or without exposure to acute stress. This study identified alterations in DNA methylation and microRNA expression linked to the 22q11.2 deletion as well as SCZ within the context of the deletion in humans. The results were then compared to the effects of the corresponding deletion and stress in the mouse model. Notably, four genes (ZBTB20, SHANK3, GRAMD1B, XKR4) overlapped across all comparisons. Pathway analysis evealed epigenetic differences in the Wnt pathway associated with stress and SCZ within the context of the deletion. These findings support the hypothesis that the onset of SCZ in individuals with 22q11.2DS may be influenced by epigenetic mechanisms, both within and outside the implicated region, under the influence of environmental stressors. If replicated, these findings could be used to develop biomarkers for early diagnosis in del22q11 carriers and to explore new targeted therapeutic strategies.