Systematic review and mega-analysis of the peripheral blood transcriptome in depression implicates dysregulation of lymphoid cells and histones.

Background: Depression has been associated with transcriptomic changes in peripheral blood. However, the contribution of specific immune cell subsets or pathways remains unclear, and findings have been variable across previous studies, which have not tended to account for sample cellular composition.

Methods: We performed a systematic review of peripheral blood transcriptome studies in depression. For the five datasets meeting criteria (total N=6,011), we performed harmonized reprocessing and cell-composition-adjusted differential gene and transcript analyses, followed by a bias- and inflation-adjusted weighted Z-score mega-analysis. We investigated the biological pathways and cell subsets implicated by the results. We also performed a sex-stratified gene network mega-analysis using consensus weighted gene co-expression network analysis (WGCNA).

Results: Few genes showed robust differential gene expression (DGE) in depression. Depression was reproducibly associated with decreases in replication-dependent histones, and with a decrease in oxidative phosphorylation pathways in females only. Cell source analyses implicated lymphoid cells (T cells and NK cells) as likely contributors to the depression differential expression signature. WGCNA mega-analysis revealed multiple consensus modules associated with depression, with a PUF60-related module upregulated in both female and male depression in sex-stratified analyses. Two genes predicted to be causally relevant to depression by transcriptome-wide association studies (GPX4 and GYPE) showed significant DGE.

Conclusions: These results are convergent with immunogenetic evidence implicating lymphoid cell dysregulation in depression, while also highlighting histone alterations as a key molecular signature in depression. They also indicate the importance of large-scale datasets for biomarker discovery in the context of heterogeneous disorders like depression.