Immune dysregulation contributes to the pathophysiology of depression and is a potential link between depression and comorbid medical conditions. DNA methylation is a dynamic transcriptional regulator of the immune system.

To study changes in DNA methylation of disease- and comorbidity-associated immune genes in patients with and without depression diagnoses from the German BiDirect Study.

We performed a cross-sectional (baseline, y0) and longitudinal (consecutive assessments at 3-year intervals, y0, y3, y6) differential methylation analyses of 382 immune-related genes associated with depression, obesity, diabetes and/or gout in 276 patients with depression and in 207 individuals without a lifetime depression diagnosis from the BiDirect Study. In addition, we applied unsupervised clustering to identify subgroups of individuals with depression based on longitudinal methylation patterns.

There were no significant methylation changes between individuals with depression and controls at baseline. Follow-up analyses used to assess the top (P < 0.05) 151 methylation probes longitudinally identified 42 CpG sites that showed time-dependent changes associated with depression, and defined 3 depression clusters with differential profiles of serum inflammation markers at baseline. The implicated genes corresponded in the majority to those associated with diabetes risk, and were enriched in processes relevant for haematopoiesis.

Our results suggest that immune dysregulation associated with DNA methylation profiles contributes to the pathophysiology of depression and is a plausible link to chronic medical conditions such as diabetes.