Associations of immunological proteins/traits with schizophrenia, major depression and bipolar disorder: a bi-directional two-sample mendelian randomization study

Benjamin I Perry, Rachel Upthegrove, Nils Kappelmann, Peter B Jones, Stephen Burgess, Golam M Khandaker

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Background: Schizophrenia, bipolar disorder and depression are associated with inflammation. However, it is unclear whether associations of immunological proteins/traits with these disorders are likely to be causal, or could be explained by reverse causality/residual confounding.

Methods: We used bi-directional two-sample Mendelian randomization (MR) and multi-variable MR (MVMR) analysis to examine evidence of causality, specificity and direction of association of 20 immunological proteins/traits (pro-inflammatory cytokines: interleukin (IL)-6, tumour necrosis factor (TNF)-α, IL-12, IL-16, IL-17, IL-18; anti-inflammatory cytokines: IL-1 receptor antagonist (RA), IL-10, IL-13; chemokines: IL-8, monocyte chemo-attractant protein-1 (MCP-1); lymphoid growth-factors: soluble (s) IL-2Rα, IL-4, IL-7, IL-9; myeloid growth-factor: IL-5; acute phase protein: C-Reactive Protein (CRP); immune cells: neutrophils, lymphocytes; neurotrophic factor: brain derived neurotrophic factor (BDNF)) with schizophrenia, major depression and bipolar disorder.

Results: Genetically-predicted IL-6 was associated with increased risk of schizophrenia in univariable MR (OR = 1.24; 95% C.I., 1.05–1.47) and with major depression in MVMR (OR = 1.08; 95% C.I., 1.03–1.12). These results survived Bonferroni-correction. Genetically-predicted sIL-2Rα (OR = 1.07; 95% C.I., 1.01–1.12) and IL-9 (OR = 1.06; 95% C.I., 1.01–1.11) were associated with increased schizophrenia risk. Genetically-predicted BDNF (OR = 0.97; 95% C.I., 0.94–1.00) and MCP-1 (OR = 0.96; 95% C.I., 0.91–0.99) were associated with reduced schizophrenia risk. However, these findings did not survive correction for multiple testing. The CRP-schizophrenia association attenuated completely after taking into account IL-6 and sIL-2Rα in MVMR (OR = 1.02; 95% C.I., 0.81–1.28). No significant associations were observed for bipolar disorder. Evidence from bidirectional MR did not support reverse causality.

Conclusions: We report evidence in support of potential causal associations of several immunological proteins/traits with schizophrenia, and of IL-6 with depression. Some of the findings did not survive correction for multiple testing and so replication in larger samples is required. Experimental studies are also required to further examine causality, mechanisms, and treatment potential for these immunological proteins/pathways for schizophrenia and depression.

Original languageEnglish
Pages (from-to)176-185
Number of pages10
JournalBrain, Behavior, and Immunity
Early online date16 Jul 2021
Publication statusPublished - Oct 2021

Bibliographical note

Funding Information:
BIP acknowledges funding support from the NIHR (Doctoral Research Fellowship, DRF-2018-11-ST2-018). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care. GMK acknowledges funding support from the Wellcome Trust (201486/Z/16/Z), the MQ: Transforming Mental Health (Data Science Award; grant code: MQDS17/40), the Medical Research Council UK (MICA: Mental Health Data Pathfinder; grant code: MC_PC_17213 and Therapeutic Target Validation in Mental Health; grant code: MR/S037675/1), and the BMA Foundation (J Moulton grant 2019). SB is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 204623/Z/16/Z). PBJ acknowledges funding from the MRC and MQ (as above), programmatic funding from NIHR (RP-PG- 0616-20003) and support from the Applied Research Collaboration East of England. RU acknowledges funding support from the NIHR (HTA grant code): 127700 and MRC (Therapeutic Target Validation in Mental Health grant code: MR/S037675/1). We would like to thank Professor Robert Dantzer, University of Texas in Houston MD Anderson Cancer Center, for his comments on a previous version of this manuscript. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. This work is licensed under a Creative Commons Attribution 4.0 International License.

Publisher Copyright:
© 2021 The Authors


  • Immune system
  • Inflammation
  • Mendelian randomization
  • bipolar disorder
  • depression
  • schizophrenia

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience


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