Applying Mendelian randomization to appraise causality in relationships between smoking, depression and inflammation

Abstract

Smoking, inflammation and depression commonly co-occur and may be mechanistically linked. However, key questions remain around the direction of association and the influence of residual confounding. We aimed to characterize the association between lifetime smoking and depression, as well as to assess the role that genetically-predicted C-reactive protein (CRP) level, (an archetypal generalized inflammatory marker) and/or IL-6 activity, as a potential explanation for this association. We performed inverse variance weighted Mendelian randomization (MR) analyses using recently published summary-level GWAS data for lifetime smoking index, CRP levels, and depression. A subset of inflammatory-related genetic variants from the lifetime smoking GWAS were also used to assess the potential inflammatory causal pathways between smoking and depression. The analysis indicated reciprocal relationships of lifetime smoking with depression (ORSmk–Dep = 2.01, 95% CI 1.71–2.37, p < 0.001; ORDep–Smk = 1.09, 95% CI 1.06–1.13, p < 0.001), CRP levels and IL-6 activity (ORSmk–CRP = 1.40, 95% CI 1.21–1.55, p < 0.001; ORCRP–Smk = 1.03, 95% CI 1.02–1.05, p < 0.001, ORIL-6/CRP–Smk = 1.06 (1.03–1.09), p < 0.001). These associations were also supported by the majority of the robust MR methods performed. We did not find evidence for a reciprocal relationship between CRP levels (using > 500 genetic instruments for CRP) and depression (ORCRP–Dep = 1.01, 95% CI 0.99–1.04; ORDep–CRP = 1.03, 95% CI 0.99–1.07). We observed little variation in the IVW estimates between smoking and depression when we limited the genetic variants assessed to those related to measures of generalized inflammation, but we found evidence for an attenuation of the smoking-depression association in multivariable mendelian randomization when adjusting for IL-6 activity, suggesting that the IL-6 pathway may be at least in part responsible for the association of smoking and depression. Our study supports potential bidirectional causal associations between lifetime smoking and depression which may be at least in part explained by the IL-6 signalling pathway. The IL-6 pathway may represent a putative therapeutic target for smoking and to mitigate the effects of smoking on depression.

Role of Inflammation in Depressive and Anxiety Disorders, Affect, and Cognition: Genetic and Non-Genetic Findings in the Lifelines Cohort Study

“…In genetic analyses, there was also little evidence of an association between CRP GRS and depression outcomes, although there was evidence suggesting GlycA GRS increases liability to MDD. The null CRP findings are consistent with previous MR studies showing no evidence of effect in MDD (54, 55, 102). However, the MR literature of CRP on depression is mixed with some studies reporting CRP to decrease (45) or increase (42) risk for depression.…”

Exploring a Potential Interaction Between the Effect of Specific Maternal Smoking Patterns and Comorbid Antenatal Depression in Causing Postpartum Depression

“… 49 An inflammatory response has been suggested as a mechanism in the signaling pathway underlying the effects of stress and depression. 50 Elevated levels of immune biomarkers in maternal serum in the final trimester of pregnancy were found to be associated with symptoms of antenatal depression. 51 Provided that smoking, antenatal depression and the immune system share a common physiological inflammatory pathway, it is plausible that they are likely to contribute to PPD.…”

The potential causal relationship between various lifestyles and depression: a univariable and multivariable Mendelian randomization study

“…Longitudinal studies suggest that smoking is a potential factor for developing depression ( 39 ). Recent MR studies indicate that smoking is a causal risk factor for diagnosed depression ( 40 ), and inflammation is likely involved in at least part of the connection between smoking and depression ( 41 ). Our UVMR showed a causal relationship between weekly alcohol consumption and never smoking with depression.…”