Role of Inflammation in Depression and Anxiety: Tests for Disorder Specificity, Linearity and Potential Causality of Association in the UK Biobank

Zheng Ye*, Nils Kappelmann, Sylvain Moser, George Davey Smith, Stephen Burgess, Peter Jones, Golam Khandaker

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

21 Citations (Scopus)
30 Downloads (Pure)


Background: Concentrations of C-reactive protein (CRP), interleukin 6 (IL-6) and other inflammatory markers are elevated in people with depression and anxiety compared to controls, but evidence for disorder-specificity, linearity and potential causality is sparse.
Methods: Using population-based data from up to 144,890 UK Biobank cohort participants, we tested associations of circulating CRP concentrations with depression and anxiety symptom scores and probable diagnosis, including tests for linearity, disorder-specificity and sex difference. We examined potential causality using 1-sample and 2-sample Mendelian randomisation (MR) analyses testing associations of genetically-predicted CRP concentration and IL-6 activity with depression and anxiety. The study was conducted from June 2019 to February 2021.
Findings: CRP concentration was associated with depressive and anxiety symptom scores and with probable diagnoses of depression and generalised anxiety disorder (GAD) in a dose-response fashion. These associations were stronger for depression than for anxiety, and for women than for men although less consistently. MR analyses provided consistent results suggesting that genetically predicted higher IL-6 activity was associated with increased risk for depressive symptoms, while genetically-predicted higher CRP concentration was associated with decreased risks of depressive and anxiety symptoms.
Interpretation: Altered activity of the IL-6/IL-6R pathway could be a risk factor for depression. The field now requires experimental studies of IL-6 modulation in humans and animal models to further examine causality, mechanisms and treatment potential. Such studies are also needed to elucidate mechanisms for divergent associations of genetically-predicted higher IL-6 activity (risk increasing) and higher CRP concentrations (protective) with depression/anxiety.
Original languageEnglish
Article number100992
Number of pages9
Early online date25 Jun 2021
Publication statusE-pub ahead of print - 25 Jun 2021


  • Depression
  • Anxiety
  • Inflammation
  • CRP
  • IL-6
  • endelian randomisation


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