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

Abstract

The increasingly compelling data supporting the involvement of immunobiological mechanisms in Major Depressive Disorder (MDD) might provide some explanation forthe 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. 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). There were three groups with major depressive disorder (MDD): treatment-resistant (n = 94), treatment-responsive (n = 47) and untreated (n = 46). Healthy controls numbered 44. Using PBMCs gene expression analysis was conducted using RNAseq to a depth of 54.5 million reads. Differential gene expression analysis was performed using DESeq2. The data showed no robust signal differentiating MDD and HCs. There was, however, significant evidence of elevated biological ageing in MDD vs HC. Biological ageing was evident in these data as a transcriptional signature of 888 age-associated genes (adjusted p < 0.05, absolute log2fold > 0.6) that also correlated strongly with chronological age (spearman correlation coefficient of 0.72). Future work should expand clinical sample sizes and reduce clinical heterogeneity. Exploration of RNA-seq signatures in other leukocyte populations and single cell RNA sequencing 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; 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).…”

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 – 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 – 166 . Dysregulation of the interactions among physiological stress systems that include inflammation, hypothalamic–pituitary–adrenal axis hyperactivity and metabolic dysregulation may partly underlie these associations 167 – 169 .…”

Cellular and immunometabolic mechanisms of inflammation in depression: Preliminary findings from single cell RNA sequencing and a tribute to Bruce McEwen

“…Studies have also examined whole genome expression including bulk RNA sequencing (RNAseq), which like whole genome expression in PBMCs or whole blood provides transcriptome profiling across immune cell types without sufficient power to detect cell-type specific expression differences. Results indicate that peripheral blood immune cells from MD patients exhibit increased activation of signaling pathways related to inflammation and innate immune responses including pathways enriched for IL-6, Type I IFN, and the TNF receptor gene as well as accelerated aging ( Spijker et al, 2010 ; Yi et al, 2012 ; Mostafavi et al, 2014 ; Guilloux et al, 2015 ; Jansen et al, 2016 ; Hori et al, 2016 ; Leday et al, 2018 ; Le et al, 2018 ; Cole et al, 2021 ). Moreover, consistent with the impact of inflammation on neurocircuits involving subcortical nuclei, gene networks interconnecting TNF and NF-kB have been linked with the morphology of the caudate ( Savitz et al, 2013 ).…”