Activated immune–inflammatory pathways are associated with long-standing depressive symptoms: Evidence from gene-set enrichment analyses in the Young Finns Study

• Inflammation has been shown to be associated with depressive symptoms, but the molecular mechanisms are not known.
• We used Gene Set Enrichment Analysis and analytical methods to examine the molecular mechanisms in depressive symptoms.
• Depressive symptoms were associated with differences in regulatory pathways that were associated with inflammatory processes.

We used genome wide expression (GWE) data of circulating blood cells and pathway analysis to investigate the inflammatory and other molecular pathways that may be associated with long-standing depressive symptoms. Participants were 607 women and 316 men (mean age 42 years) from the Young Finns Study who participated in three consecutive study phases in 2001, 2007 and 2012. Using Gene-set enrichment analyses (GSEA) we focused our analyses to pathways (available in MSigDB database) that are likely to affect immunological and inflammatory processes. GSEA were performed for blood cell GWE data in 2012. Depressive symptoms were assessed using a modified 21-item Beck Depression Inventory in each of the three study phases. Participants who scored in the top quartile of depressive symptoms in each of the three measurement points (n = 191) differed from other participants (n = 732) in several gene–set pathways related to inflammatory processes or immune-inflammatory signaling including interleukin (IL-1) pathway, and pathways related to various immuno-inflammatory processes, such as toll-like, the NEF protein, the nuclear factor kB, the kinase AKT and the mature B cell antigen receptor pathway (false discovery rates, FDRs < 0.12). The results provide novel genome wide molecular evidence that support the association between chronic depressive symptoms and altered immune-inflammatory regulation.