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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 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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Depression as a risk factor for Alzheimer’s disease: A human post-mortem study
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“…there are several risk factors associated with alcohol consumption and depression, including inflammation levels [inflammatory biomarkers IL-6 (24) and C-reactive protein (25)], acid sphingomyelinase (16), body mass index (26), body fat percentage (BFP) (27), and diet-related metabolites (28).”
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Interleukin-6 signaling pathway in Mendelian randomization: A 10-year bibliometric analysis
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“Multiple Mendelian randomization analyses have demonstrated the connection between IL-6 signaling pathway and various disorders, including Depression, [16] rheumatoid arthritis, [17] systemic lupus erythematosus, [18] Breast Cancer, [19] etc.”
BackgroundEffect of negative mood, serum inflammatory factors, miR-155, and brain-derived neurotrophic factor
Zhang, Q., Zhao, Y., & Cheng, G. (2025) · World Journal of Psychiatry · doi:10.5498/wjp.v15.i2.99573 · Cited by 4
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Genetic predisposition to inflammation and psychopathology: A transdiagnostic network analysis
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The role of IL-6 in rheumatoid arthritis comorbidity and implications for therapy
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“Campbell et al. (2014) concluded from their murine studies that many neuropathogenic effects of IL-6 are mediated through trans-signalling [134], and a Mendelian randomisation study in 2021 provided evidence for a causal effect of sIL-6R on depression in humans [135].”
Li, Y., Zhang, Y., Liu, W., & Chen, Z. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.119488 · Cited by 4
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Metadata
- 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
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