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 known. In this study we use Mendelian Randomization to examine the possibility of a causal relationship between IL-6 signaling pathways 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 (Odds Ratio: 1.023 (95% Confidence Interval: 1.006-1.039), p=0.006). Exploratory analysis demonstrate that the relationship could be consistent with either decreased classical signaling or increased trans signaling as the underlying mechanism.
Discussion
These results support 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.