Dysmaturational Longitudinal Epigenetic Aging During Transition to Psychosis

Psychosis frequently occurs during adolescence and young adulthood, possibly as a result of gene-environment interactions, mediated by epigenetic mechanisms such as DNA methylation. Methylation patterns can be leveraged to predict epigenetic age in order to identify anomalies in aging trajectories that may be associated with the emergence of psychosis. Thus, epigenetic age may provide a measurable surrogate of psychotic risk or psychosis' emergence, and shed light on the neurodevelopmental model of psychosis. In this study, we present the first longitudinal analysis of epigenetic age trajectory during conversion to psychosis in a population at ultra-high-risk, with available genome-wide methylation DNA at two time points, at baseline and after one year of follow-up (N = 38 × 2). After predicting epigenetic age, we computed epigenetic age gap as the cross-sectional difference between real age and predicted age, and (longitudinal) epigenetic age acceleration as the derivative of predicted age with respect to time. At baseline, future converters were 2.7 years younger than nonconverters and this difference disappeared at follow-up, when some converted to psychosis. This is because during conversion to psychosis, the epigenetic age of converters accelerated by 2.8 years/year compared to nonconverters. This acceleration was robust with a strictly positive 95% confidence interval, and held its significance after adjustment for age, sex, and cannabis intake. The methylation sites most associated with aging were on genes also linked with schizophrenia and neurodevelopmental disorders. This accelerated age trajectory, following a previous deceleration, may therefore reflect dysmaturational processes.