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 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.
Competing Interest Statement
EB has recently consulted Boehringer Ingelheim, SR One, Novartis, GlaxoSmithKline, Sosei Heptares and Monument Therapeutics. RAB and EB hold equity in and are cofounders of Centile Bioscience Inc. CE and MEL have no conflict of interest to declare.
Funding Statement
CE was supported by a Dr Manmohan Singh scholarship, St John's College, University of Cambridge. MEL was supported by an NIHR Clinical Lectureship. This work was also supported by the ImmunoMIND hub (MR/Z50354X/1) as part of the UKRI Mental Health Platform. All research at the Department of Psychiatry in the University of Cambridge is supported by the NIHR Cambridge Biomedical Research Centre (NIHR203312) and the NIHR Applied Research Collaboration East of England. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
This is a meta-analysis and most datasets are publicly available online. dbGaP data were obtained through application via the dbGaP web portal (https://www.ncbi.nlm.nih.gov/gap/ddb/), study accession: phs000486.v1.p1, with approval for re-analysis granted under project number 28948.
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Data Availability
Code to reproduce the individual dataset analyses, meta-analyses and figures is available at https://github.com/lynalllab/depression_transcriptome. At the Zenodo repository https://doi.org/10.5281/zenodo.15290507, we provide genome-wide gene- and transcript- level summary statistics; where permitted, we also supply harmonized processed individual- level count matrices along with estimated cell counts and metadata (where permitted).
https://doi.org/10.5281/zenodo.15290507
https://github.com/lynalllab/depression_transcriptome
