No evidence for differential gene expression in major depressive disorder PBMCs, but robust evidence of elevated biological ageing

Abstract

Background The increasingly compelling data supporting the involvement of immunobiological mechanisms in Major Depressive Disorder (MDD) might provide some explanation of the variance in this heterogeneous condition. Peripheral blood measures of cytokines and chemokines constitute the bulk of evidence with consistent meta-analytic data implicating raised proinflammatory cytokines such as IL6, IL1β and TNF. Among the potential mechanisms linking immunobiological changes to affective neurobiology is the accelerated biological ageing seen in MDD, particularly via the senescence associated secretory phenotype (SASP). However, the cellular source of immunobiological markers remains unclear. Aims Pre-clinical evidence suggests a role for peripheral blood mononuclear cells (PBMC), thus here we aimed to explore the transcriptomic profile using RNA sequencing in PBMCs in a clinical sample of people with various levels of depression and treatment response comparing it with that in healthy controls (HCs). Method Transcriptomic analysis of peripheral blood mononuclear cells. Results The data showed no robust signal differentiating MDD and HCs. There was, however, significant evidence of elevated biological ageing in MDD vs HC. Conclusions Future work should endeavour to expand clinical sample sizes and reduce clinical heterogeneity. The exploration of RNA-seq signatures in other leukocyte populations and advances in RNA sequencing at the level of the single cell may help uncover more subtle differences. However, currently the subtlety of any PBMC signature mitigates against its convincing use as a diagnostic or predictive biomarker.

PTSD, major depression, and advanced transcriptomic age in brain tissue

“…These results are consistent with prior studies showing associations between multiple psychiatric phenotypes, including PTSD, AUD, MDD, and anxiety, and advanced DNAm age in blood and brain tissue (Bøstrand et al, 2022; Han et al, 2018; Marečková et al, 2020; Protsenko et al, 2021; Wolf et al, 2018; 2021) and with research suggesting associations between PTSD and MDD and transcriptomic age in blood (Carter et al, 2019; Cole et al, 2021; Kuan et al, 2021). This study extends this association to the brain transcriptome, demonstrating the robustness of these associations across the epigenome and tissue types.…”

“…Kuan et al (2021) reported significantly higher age‐adjusted RNA age estimates (using the Ren & Kuan, 2020 algorithm) in current PTSD cases compared to individuals without a current or prior PTSD diagnosis among 324 World Trade Center responders. Similarly, Cole et al (2021) found that individuals with MDD were more likely to have over‐estimated transcriptomic age relative to chronological age as compared to healthy controls; transcriptomic age was measured using a novel index derived from gene expression values obtained in peripheral blood mononuclear cells. In addition, one study calculated RNA age using microarray expression (not sequence) data from whole blood samples and found that depression during early adulthood was associated with advanced RNA age in African Americans (Carter et al, 2019).…”

Blood transcriptome analysis suggests an indirect molecular association of early life adversities and adult social anxiety disorder by immune-related signal transduction

“…Investigating gene expression of all participants, visual inspection of the PCA revealed no obvious grouping of samples (Fig S5). This is in line with rather subtle gene expression changes that one may expect in blood in the context of mental disorders [51,52]. Analyzing differential gene expression using DESeq2 [39], 13 significantly (FDR-corrected p ≤ 0.1) differentially expressed genes (DEGs) were identified which had a |l2fc| ≥ 0.3 with respect to SAD (Fig.…”

Immune targets for therapeutic development in depression: towards precision medicine

“…Beyond the impact of psychiatric symptoms on the morbidity and mortality associated with MDD, patients with depression also manifest a twofold to fourfold higher risk for cardiovascular disorders 160 , and have poorer outcomes during comorbid heart failure, stroke and peripheral artery disease [161][162][163] . Moreover, MDD is associated with exaggerated biological ageing: these individuals have premature decreases in leukocyte telomere length (a marker of cellular age that predicts several ageing-related diseases and early mortality) and increases in senescence-related gene transcription and molecular secretion patterns in physiological stress and inflammatory systems [164][165][166] . Dysregulation of the interactions among physiological stress systems that include inflammation, hypothalamic-pituitaryadrenal axis hyperactivity and metabolic dysregulation may partly underlie these associations [167][168][169] .…”