Epigenetic signatures in children and adolescents at familial high risk: linking early-life environmental exposures to psychopathology

Background This study investigates the relationship between environmental risk factors and severe mental disorders using genome-wide methylation data. Methylation profile scores (MPS) and epigenetic clocks were utilized to analyze epigenetic alterations in a cohort comprising 211 individuals aged 6–17 years. Participants included offspring of schizophrenia (n = 30) and bipolar disorder (n = 82) patients, and a community control group (n = 99). The study aimed to assess differences in MPS indicative of intrauterine stress and epigenetic aging across familial risk groups, and their associations with cognition, prodromal psychotic symptoms, and global functioning through statistical models. Results Individuals at high familial risk demonstrated significant epigenetic alterations associated with pre-pregnancy maternal overweight/obesity, pre-eclampsia, early preterm birth and higher birth weight (p.adj ≤ 0.001) as well as decelerated epigenetic aging in the Horvath and Hannum epigenetic clocks (p.adj ≤ 0.005). Among offspring of schizophrenia patients, more severe positive and general prodromal psychotic symptoms correlated with MPS related to maternal pre-pregnancy BMI and overweight/obesity (p.adj ≤ 0.008) as well as with accelerated epigenetic aging across all examined epigenetic clocks (p.adj ≤ 0.012). Conclusions These findings underscore the potential of methylation analysis to quantify persistent effects of intrauterine events and their influence on the onset of psychotic symptoms, particularly in high-risk populations. Further research is essential to elucidate the underlying biological mechanisms during critical early stages of neurodevelopment.