DNA methylation age acceleration, depression and anxiety: evidence from a longitudinal adolescent cohort study (SCAMP) and Mendelian Randomisation

Background DNA methylation (DNAm) based age acceleration is an indicator of biological ageing. However, it is unclear how age acceleration is linked to mental health in adolescents. We examined the longitudinal associations between DNAm age acceleration and depression and anxiety in adolescents. We also triangulated the evidence using Mendelian Randomisation (MR). Methods We analysed a subsample of adolescents (n=261) from a London-based adolescent cohort study. DNAm profile was generated from saliva samples collected at ages 11-12 years. DNAm age acceleration measures were derived from Horvath, PhenoAge, and PedBE clocks. Depressive and anxiety symptoms were measured at ages 13-15 years, using the Patient Health Questionnaire and Generalised Anxiety Disorder scale, respectively. The associations between DNAm age acceleration and depressive and anxiety symptoms were assessed using logistic regression. We also conducted a two-sample MR to investigate the potential causal relationship between Horvath and PhenoAge acceleration and depression and anxiety. Results We found that PhenoAge age acceleration was associated with higher severity levels of depressive symptoms (OR=1.04, 95% CI 1.01, 1.08) and clinically significant depressive symptoms (OR=1.05, 95% CI 1.01, 1.10). None of these three clocks was associated with anxiety outcomes. MR suggested a potential causal relationship between PhenoAge age acceleration and depression (Inverse variance weighted OR = 1.01, 95% CI 1.00, 1.02). Conclusions PhenoAge acceleration at ages 11-12 years was associated with depressive symptoms at ages 13-15 years. The association patterns are consistent between longitudinal and MR analyses. PhenoAge acceleration may represent a potential early biomarker for subsequent depressive symptoms in adolescents.