Fig. 1: Study design of investigating antidepressant exposure and DNA methylation.

Data: Participants in Generation Scotland (GS) provided blood samples from which DNA methylation was measured. Their antidepressant exposure status was measured using both self-report questionnaires and prescription-derived measures. Prescription-derived measures: Repeated regular prescriptions over time (X axis) for antidepressants (purple bars) are merged to form active antidepressant treatment periods (blue bars). Individuals in an active treatment period at the time of blood sample (black cross) are classed as antidepressant exposed. Methylome-wide association studies: A methylome-wide association study (MWAS), subsequent regional analysis and functional annotation was performed for both measures of antidepressant exposure. Additionally, an enrichment analysis was done using MBD-Sequencing data in the Netherlands Depression and Anxiety (NESDA) cohort for the self-report antidepressant exposure. Methylation Profile Score: Weights for a methylation profile score (MPS) of self-reported antidepressant exposure was calculated in GS using a least absolute shrinkage and selection operator (LASSO) model. Eight independent datasets then tested the association of this MPS with self-reported antidepressant exposure. Created in BioRender. Davyson, E. (2024) https://BioRender.com/s43g100.