Depression and interleukin-6 signaling: A Mendelian Randomization study

Kristen M. Kelly; Jennifer A. Smith; Briana Mezuk

doi:10.1016/j.bbi.2021.02.019

Depression and interleukin-6 signaling: A Mendelian Randomization study

Kristen M. Kelly^*, Jennifer A. Smith, Briana Mezuk

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Pages (from-to)	106-114
Number of pages	9
Journal	Brain, Behavior, and Immunity
Volume	95
DOIs	https://doi.org/10.1016/j.bbi.2021.02.019
Publication status	Published - Jul 2021

Bibliographical note

Funding Information:
KM Kelly was supported by the National Human Genome Research Institute (National Institutes of Health) Training Program in Genomic Science at the University of Michigan ( T32-HG00040 ).

Funding Information:
B Mezuk was supported by National Institute of Mental Health (National Institutes of Health) K01-MH093642-A1.

Funding Information:
KM Kelly was supported by the National Human Genome Research Institute (National Institutes of Health) Training Program in Genomic Science at the University of Michigan (T32-HG00040). B Mezuk was supported by National Institute of Mental Health (National Institutes of Health) K01-MH093642-A1. This research has been conducted using the UK Biobank Resource under Application Number 41812. We would also like to thank the authors and cohorts from the following GWAS studies for generously making their GWAS coefficients available:, Folkersen et al 2017 (DOI: 10.1371/journal.pgen.1006706) (IMPROVE Consortium). Sun et al 2018 (DOI: 10.1038/s41586-018-0175-2) (INTERVAL Study). Suhre et al 2017 (DOI: 10.1038/ncomms14357) (KORA cohort). van Dongen et al 2014 (DOI: 10.1007/s10519-014-9656-8) (Netherlands Twin Register). Wray et al 2018 (DOI: 10.1038/s41588-018-0090-3) (Psychiatric Genomics Consortium). Yao et al 2018 (DOI: 10.1038/s41467-018-05512-x) (Framingham Heart Study). An earlier version of this analysis appeared in the poster Depression and the soluble interleukin-6 receptor: A Mendelian Randomization. The poster was presented at the 2019 World Congress of Psychiatric Genetics October 26-31 in Anaheim, California. An earlier version of this analysis was included in KM Kelly's dissertation, which was submitted to the University of Michigan on August 17, 2020. KM Kelly would like to thank Drs. Pat Peyser, Michael Boehnke, and Laura Scott for their contributions to the development and refinement of this analysis as members of her dissertation committee, and to thank Drs. Minjung Kho and Wei Zhao for their assistance and guidance in working with tools and datasets used in the analysis.

Publisher Copyright:
© 2021 The Authors

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Funding

KM Kelly was supported by the National Human Genome Research Institute (National Institutes of Health) Training Program in Genomic Science at the University of Michigan ( T32-HG00040 ). B Mezuk was supported by National Institute of Mental Health (National Institutes of Health) K01-MH093642-A1. KM Kelly was supported by the National Human Genome Research Institute (National Institutes of Health) Training Program in Genomic Science at the University of Michigan (T32-HG00040). B Mezuk was supported by National Institute of Mental Health (National Institutes of Health) K01-MH093642-A1. This research has been conducted using the UK Biobank Resource under Application Number 41812. We would also like to thank the authors and cohorts from the following GWAS studies for generously making their GWAS coefficients available:, Folkersen et al 2017 (DOI: 10.1371/journal.pgen.1006706) (IMPROVE Consortium). Sun et al 2018 (DOI: 10.1038/s41586-018-0175-2) (INTERVAL Study). Suhre et al 2017 (DOI: 10.1038/ncomms14357) (KORA cohort). van Dongen et al 2014 (DOI: 10.1007/s10519-014-9656-8) (Netherlands Twin Register). Wray et al 2018 (DOI: 10.1038/s41588-018-0090-3) (Psychiatric Genomics Consortium). Yao et al 2018 (DOI: 10.1038/s41467-018-05512-x) (Framingham Heart Study). An earlier version of this analysis appeared in the poster Depression and the soluble interleukin-6 receptor: A Mendelian Randomization. The poster was presented at the 2019 World Congress of Psychiatric Genetics October 26-31 in Anaheim, California. An earlier version of this analysis was included in KM Kelly's dissertation, which was submitted to the University of Michigan on August 17, 2020. KM Kelly would like to thank Drs. Pat Peyser, Michael Boehnke, and Laura Scott for their contributions to the development and refinement of this analysis as members of her dissertation committee, and to thank Drs. Minjung Kho and Wei Zhao for their assistance and guidance in working with tools and datasets used in the analysis.

Funders	Funder number
National Institutes of Health
National Institute of Mental Health	K01MH093642, 41812
National Human Genome Research Institute
University of Michigan	T32-HG00040

Keywords

Depression
Inflammation
Interleukin-6
Mendelian Randomization
sIL-6R
Soluble interleukin-6 receptor

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bbi.2021.02.019

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Cite this

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title = "Depression and interleukin-6 signaling: A Mendelian Randomization study",

abstract = "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.",

keywords = "Depression, Inflammation, Interleukin-6, Mendelian Randomization, sIL-6R, Soluble interleukin-6 receptor",

author = "Kelly, \{Kristen M.\} and Smith, \{Jennifer A.\} and Briana Mezuk",

note = "Funding Information: KM Kelly was supported by the National Human Genome Research Institute (National Institutes of Health) Training Program in Genomic Science at the University of Michigan ( T32-HG00040 ). Funding Information: B Mezuk was supported by National Institute of Mental Health (National Institutes of Health) K01-MH093642-A1. Funding Information: KM Kelly was supported by the National Human Genome Research Institute (National Institutes of Health) Training Program in Genomic Science at the University of Michigan (T32-HG00040). B Mezuk was supported by National Institute of Mental Health (National Institutes of Health) K01-MH093642-A1. This research has been conducted using the UK Biobank Resource under Application Number 41812. We would also like to thank the authors and cohorts from the following GWAS studies for generously making their GWAS coefficients available:, Folkersen et al 2017 (DOI: 10.1371/journal.pgen.1006706) (IMPROVE Consortium). Sun et al 2018 (DOI: 10.1038/s41586-018-0175-2) (INTERVAL Study). Suhre et al 2017 (DOI: 10.1038/ncomms14357) (KORA cohort). van Dongen et al 2014 (DOI: 10.1007/s10519-014-9656-8) (Netherlands Twin Register). Wray et al 2018 (DOI: 10.1038/s41588-018-0090-3) (Psychiatric Genomics Consortium). Yao et al 2018 (DOI: 10.1038/s41467-018-05512-x) (Framingham Heart Study). An earlier version of this analysis appeared in the poster Depression and the soluble interleukin-6 receptor: A Mendelian Randomization. The poster was presented at the 2019 World Congress of Psychiatric Genetics October 26-31 in Anaheim, California. An earlier version of this analysis was included in KM Kelly's dissertation, which was submitted to the University of Michigan on August 17, 2020. KM Kelly would like to thank Drs. Pat Peyser, Michael Boehnke, and Laura Scott for their contributions to the development and refinement of this analysis as members of her dissertation committee, and to thank Drs. Minjung Kho and Wei Zhao for their assistance and guidance in working with tools and datasets used in the analysis. Publisher Copyright: {\textcopyright} 2021 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = jul,

doi = "10.1016/j.bbi.2021.02.019",

language = "English",

volume = "95",

pages = "106--114",

journal = "Brain, Behavior, and Immunity",

issn = "0889-1591",

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AU - Smith, Jennifer A.

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N1 - Funding Information: KM Kelly was supported by the National Human Genome Research Institute (National Institutes of Health) Training Program in Genomic Science at the University of Michigan ( T32-HG00040 ). Funding Information: B Mezuk was supported by National Institute of Mental Health (National Institutes of Health) K01-MH093642-A1. Funding Information: KM Kelly was supported by the National Human Genome Research Institute (National Institutes of Health) Training Program in Genomic Science at the University of Michigan (T32-HG00040). B Mezuk was supported by National Institute of Mental Health (National Institutes of Health) K01-MH093642-A1. This research has been conducted using the UK Biobank Resource under Application Number 41812. We would also like to thank the authors and cohorts from the following GWAS studies for generously making their GWAS coefficients available:, Folkersen et al 2017 (DOI: 10.1371/journal.pgen.1006706) (IMPROVE Consortium). Sun et al 2018 (DOI: 10.1038/s41586-018-0175-2) (INTERVAL Study). Suhre et al 2017 (DOI: 10.1038/ncomms14357) (KORA cohort). van Dongen et al 2014 (DOI: 10.1007/s10519-014-9656-8) (Netherlands Twin Register). Wray et al 2018 (DOI: 10.1038/s41588-018-0090-3) (Psychiatric Genomics Consortium). Yao et al 2018 (DOI: 10.1038/s41467-018-05512-x) (Framingham Heart Study). An earlier version of this analysis appeared in the poster Depression and the soluble interleukin-6 receptor: A Mendelian Randomization. The poster was presented at the 2019 World Congress of Psychiatric Genetics October 26-31 in Anaheim, California. An earlier version of this analysis was included in KM Kelly's dissertation, which was submitted to the University of Michigan on August 17, 2020. KM Kelly would like to thank Drs. Pat Peyser, Michael Boehnke, and Laura Scott for their contributions to the development and refinement of this analysis as members of her dissertation committee, and to thank Drs. Minjung Kho and Wei Zhao for their assistance and guidance in working with tools and datasets used in the analysis. Publisher Copyright: © 2021 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/7

Y1 - 2021/7

N2 - 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.

AB - 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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KW - Inflammation

KW - Interleukin-6

KW - Mendelian Randomization

KW - sIL-6R

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Depression and interleukin-6 signaling: A Mendelian Randomization study

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

Persistent URL (handle)

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Cite this