DOI: 10.5281/zenodo.10698979
title: Normalized and batch-corrected concentration of 43 immune markers from 237 subjects with stress-related mental disorders and 36 healthy controls

description: Abstract

In a subset of patients with mental disorders, such as depression, low-grade inflammation and altered immune marker concentrations are observed. However, these immune alterations are often assessed by only one data type and small markers panels. Here, we used a transdiagnostic approach and combined data from two cohorts to define subgroups of depression symptoms across the diagnostic spectrum through a large-scale multi-omics clustering approach in 237 individuals. The method incorporated age, body mass index (BMI), 43 plasma immune markers and RNA-seq data from peripheral mononuclear blood cells (PBMCs). Our initial clustering revealed four clusters, including two immune-related depression symptom clusters characterized by elevated BMI, higher depression severity and elevated levels of immune markers such as interleukin-1 receptor antagonist (IL-1RA), C-reactive protein (CRP) and C-C motif chemokine 2 (CCL2 or MCP-1). In contrast, the RNA-seq data mostly differentiated a cluster with low depression severity, enriched in brain related gene sets. This cluster was also distinguished by electrocardiography data, while structural imaging data revealed differences in ventricle volumes across the clusters. Incorporating predicted cell type proportions into the clustering resulted in three clusters, with one showing elevated immune marker concentrations. The cell type proportion and genes related to cell types were most pronounced in an intermediate depression symptoms cluster, suggesting that RNA-seq and immune markers measure different aspects of immune dysregulation. Lastly, we found a dysregulation of the SERPINF1/VEGF-A pathway that was specific to dendritic cells by integrating immune marker and RNA-seq data. This shows the advantages of combining different data modalities and highlights possible markers for further stratification research of depression symptoms.

Methods

The normalized and batch-corrected concentration of 43 immune markers from 237 subjects with stress-related mental disorders and 36 healthy controls was determined in plasma.

- blood was collected in the morning under fasted conditions and plasma stored at -80°C until further processing- samples were randomized into 96 well plates- immune marker concentration was measured with the Meso Scale Diagnostics V-PLEX Human Biomarker 54-Plex Kit and the MESO QuickPlex SQ 120 imager according to the manufacturer's instructions- additionally, high-sensitivity C-reactive protein (Tecan Group Ltd.), cortisol (Tecan Group Ltd.), interleukin (IL)-6 (Thermo Fisher Scientific), IL-6 soluble receptor (Thermo Fisher Scientific) and IL-13 (Thermo Fisher Scientific) was measured via ELISA according to the manufacturer's instructions- values below the detection limit in markers measured with ELISA were set to zero and values above the detection limit to the upper limit- the data was quantile-normalized (values were ranked and mapped to the quantiles of a standard normal distribution)- the normalized concentration was corrected for the biobank storage position (batch_variable) via a linear model and the residuals reported as the concentration

The following markers were measured:fibroblast growth factor 2 (FGF2 or bFGF), cortisol, C-C motif chemokine 11 (CCL11 or eotaxin), CCL26 (eotaxin-3), vascular endothelial growth factor receptor 1 (VEGFR1 or Flt-1), hsCRP, intercellular adhesion molecule (ICAM)-1, interferon (IFN)-gamma, IL-1alpha, IL-1 receptor antagonist (IL-1RA), IL-10, IL-12/IL-23p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, IL-17B, IL-2, IL-27, IL-31, IL-5, IL-6 high sensitivity (IL-6HS), IL-7, IL-8HS, C-X-C motif chemokine 10 (CXCL10 or IP-10), CCL2  (MCP-1), CCL13 (MCP-4), CCL22 (MDC), CCL3 (MIP-1alpha), CCL4 (MIP-1beta), placental growth factor (PlGF), serum amyloid A (SAA), sIL-6R, CCL17 (TARC), angiopoietin-1 receptor (Tie-2), tumor necrosis factor (TNF or TNF-alpha), lymphotoxin-alpha (LT-alpha or TNF-beta), thymic stromal lymphopoietin (TSLP), vascular cell adhesion protein 1 (VCAM-1), vascular endothelial growth factor (VEGF)-A-HS, VEGF-C, VEGF-D

The data is provided as a tab separated file.