Depression and Interleukin-6 Signaling: A Mendelian Randomization Study
Open accessAbstract
BACKGROUND: A large body of research has reported associations between depression and elevated interleukin-6 (IL-6), a cytokine with several roles including pro-inflammatory signaling. The nature and directionality of this relationship are not yet clear. In this study we use Mendelian Randomization to examine the possibility of a causal relationship between IL-6 and depressive symptoms, and to explore multiple signaling pathways that could serve as mechanisms for this relationship. METHODS: This study uses a two-sample Mendelian Randomization design. Data come from the UK Biobank (n = 89,119) and published summary statistics from six existing GWAS analyses. The primary analysis focuses on the soluble interleukin-6 receptor (sIL-6R), which is involved in multiple signaling pathways. Exploratory analyses use C-reactive protein (CRP) and soluble glycoprotein 130 (sgp130) to further examine potential underlying mechanisms. RESULTS: Results are consistent with a causal effect of sIL-6R on depression (PCA-IVW Odds Ratio: 1.023 (95% Confidence Interval: 1.006-1.039), p = 0.006). Exploratory analyses demonstrate that the relationship could be consistent with either decreased classical signaling or increased trans signaling as the underlying mechanism. DISCUSSION: These results strengthen the body evidence implicating IL-6 signaling in depression. When compared with existing observational and animal findings, the direction of these results suggests involvement of IL-6 trans signaling. Further study is needed to examine whether IL6R genetic variants might influence IL-6 trans signaling in the brain, as well as to explore other potential pathways linking depression and inflammation.
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In depressed patients, sIL-6R levels were reported increased, with elevated levels of both IL-6 and sIL-6R persisting after the start of antidepressant treatment.
“In addition to increased IL-6 levels, sIL-R6 levels were reported in depressed patients, with elevated levels of both persisting even after the start of antidepressant treatment [87,88].”
From Selected biomarkers of depression: what are the effects of cytokines and inflammation (2022) · cites this paper as [88]
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- Authors
- Kelly, K. M., Smith, J. A., & Mezuk, B.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Kelly, Kristen M.
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2021-07
- Volume
- 95
- Pages
- 106-114
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC11081733
- OpenAlex
- W3132094446
- Cited by
- 117
- References
- 90
- Citations by year
- 2026: 23 · 2025: 22 · 2024: 34 · 2023: 20 · 2022: 15 · 2021: 3
- FWCI
- 5.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Brain Behavior and Immunity (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- VU Research Portal (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- National Institute of Mental Health (K01-MH093642-A1, 41812)
- University of Michigan (T32-HG00040)
- National Institutes of Health
- National Human Genome Research Institute (T32-HG00040)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- depression, interleukin-6, IL-6 signaling, soluble IL-6 receptor, trans-signaling, C-reactive protein, soluble glycoprotein 130, inflammation, causal relationship, genetic variants
- MeSH terms
- Animals, Depression, Interleukin-6, Receptors, Interleukin-6, Cytokine Receptor gp130, Mendelian Randomization Analysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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