A systematic review and meta-analysis of epigenetic clocks in schizophrenia

Evidence suggests that schizophrenia (SZ) is associated with accelerated biological aging. DNA methylation can be used as an indicator of biological aging by means of epigenetic clock estimates. The aim of this systematic review and meta-analysis was to investigate the association between SZ and different epigenetic clocks. Search terms were applied in different databases: Embase, MEDLINE (EBSCO), Cochrane Central Register of Controlled Trials, PubMed, PsychINFO and Web of Science. To assess for risk of bias we utilized an adapted version of the Newcastle-Ottawa Scale. Meta-analyses were conducted using the random effects model and meta-regressions were used to assess factors associated with heterogeneity. Eight studies were included (Controls, n = 3394; SZ subjects, n = 3096), which analyzed five different epigenetic clocks. Overall meta-analysis revealed no significant differences between SZ and controls on epigenetic aging (Standardized Mean Difference – SMD = −0.21; p = 0.13). However, epigenetic clock method was a significant moderator of heterogeneity (p = 0.004). Using Horvath's clock as reference, higher SMD's were found for PhenoAge and Intrinsic epigenetic age acceleration (IEAA) clocks. In a stratified meta-analysis restricted to the two clocks mentioned above, a significant accelerating effect was found in patients with SZ when compared to controls (SMD = 0.29; p = 0.003). Our findings suggest that the method of epigenetic clocks is a critical factor associated with estimates of aging acceleration in SZ. However, more studies are needed to confirm these findings and in order to evaluate a possible minor effect in overall analysis.