Systematic Review and Mega-Analysis of the Peripheral Blood Transcriptome in Depression Implicates Dysregulation of Lymphoid Cells and Histones

Clinical Snapshot

Key Findings

• P Value: Not reported in abstract

• Effect Size: Few genes showed robust differential expression; specific effect sizes not reported in abstract

• Primary Outcome: Differential gene expression in peripheral blood associated with depression

• Nnt Or Sensitivity: Not applicable - biomarker discovery study

• Confidence Interval: Not reported in abstract

Clinical Application

Currently research-only; transcriptomic analysis not routinely available in clinical practice Relevant for Australian psychiatric research and potential future biomarker development; aligns with RANZCP interest in biological psychiatry Patients with depression, particularly relevant for understanding biological mechanisms

Abstract

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 5 datasets meeting criteria (total N = 6011), 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 coexpression 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 natural killer 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 such as depression.

References

1. 1.Erady, C., Bethlehem, R., Bullmore, E., & Lynall, M. E. (2026). Systematic Review and Mega-Analysis of the Peripheral Blood Transcriptome in Depression Implicates Dysregulation of Lymphoid Cells and Histones. Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2025.09.008