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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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Cites
Bowden, J., Davey Smith, G., & Burgess, S. (2015) · International Journal of Epidemiology · doi:10.1093/ije/dyv080 · Cited by 9,816
The UK Biobank resource with deep phenotyping and genomic data
Bycroft, C., Freeman, C., Petkova, D., Band, G., Elliott, L. T., Sharp, K., Motyer, A., Vukcevic, D., Delaneau, O., O’Connell, J., et al. (2018) · Nature · doi:10.1038/s41586-018-0579-z · Cited by 8,876
Molecular Mechanisms of Depression: Perspectives on New Treatment Strategies
Lang, U. E., & Borgwardt, S. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350094 · Cited by 8,525
From inflammation to sickness and depression: when the immune system subjugates the brain
Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2297 · Cited by 7,395
Mendelian randomization: genetic anchors for causal inference in epidemiological studies
Davey Smith, G., & Hemani, G. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu328 · Cited by 4,677
Mendelian randomization: Using genes as instruments for making causal inferences in epidemiology
Lawlor, D. A., Harbord, R. M., Sterne, J. A. C., Timpson, N., & Davey Smith, G. (2008) · Statistics in Medicine · doi:10.1002/sim.3034 · Cited by 4,618
Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants
Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., Dulawa, S., Weisstaub, N., Lee, J., Duman, R., Arancio, O., et al. (2003) · Science · doi:10.1126/science.1083328 · Cited by 4,321
Inflammation and Its Discontents: The Role of Cytokines in the Pathophysiology of Major Depression
Miller, A. H., Maletic, V., & Raison, C. L. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.11.029 · Cited by 3,848
The pro- and anti-inflammatory properties of the cytokine interleukin-6
Scheller, J., Chalaris, A., Schmidt-Arras, D., & Rose-John, S. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.01.034 · Cited by 3,212
Cytokines sing the blues: inflammation and the pathogenesis of depression
Raison, C. L., Capuron, L., & Miller, A. H. (2006) · Trends in Immunology · doi:10.1016/j.it.2005.11.006 · Cited by 3,009
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Milaneschi, Y., Kappelmann, N., Ye, Z., Lamers, F., Moser, S., Jones, P. B., Burgess, S., Penninx, B. W. J. H., & Khandaker, G. M. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01188-w · Cited by 385
“Similar divergent MR results have also been reported for schizophrenia and depression, suggesting a protective effect of CRP and a riskincreasing effect of soluble IL-6 receptor (IL-6R) on schizophrenia and depression risk, respectively [45, 46].”
ResultSelected biomarkers of depression: what are the effects of cytokines and inflammation
Harsanyi, S., Kupcova, I., Danisovic, L., & Klein, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms24010578 · Cited by 299
“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].”
BackgroundAndreassen, O. A., Hindley, G., Frei, O., & Smeland, O. B. (2023) · World Psychiatry · doi:10.1002/wps.21034 · Cited by 275
Hamilton, F., Thomas, M., Arnold, D., Palmer, T., Moran, E., Mentzer, A. J., Maskell, N. A., Baillie, J. K., Summers, C., Hingorani, A. D., et al. (2023) · PLoS Medicine · doi:10.1371/journal.pmed.1004174 · Cited by 144
“We did not identify a robust effect on sepsis when instrumenting gp130, although there is much less evidence that genetic variation at this locus affects IL-6 signalling [45].”
BackgroundYe, Z., Kappelmann, N., Moser, S., Smith, G. D., Burgess, S., Jones, P. B., & Khandaker, G. M. (2021) · EClinicalMedicine · doi:10.1016/j.eclinm.2021.100992 · Cited by 105
“Taken together, these findings also align with a recent MR study on the effects of genetically predicted sIL-6R, sgp130 (an inhibitor of IL-6 trans-signalling [51]), and CRP on recurrent depression, which suggested that increased IL-6 trans-signalling or decreased IL-6 classic signalling could be responsible for a ris…”
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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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