Disentangling the effects of nicotine versus non-nicotine constituents of tobacco smoke on major depressive disorder: A multivariable Mendelian randomisation study

Background and aims
There is growing evidence that tobacco smoking causes depression, but it is unclear which constituents of tobacco smoke (e.g. nicotine, carbon monoxide) may be responsible. We used Mendelian randomisation (MR) to measure the independent effect of nicotine on depression, by adjusting the effect of circulating nicotine exposure [via nicotine metabolite ratio (NMR)] for the overall effect of smoking heaviness [via cigarettes per day (CPD)] to account for the non-nicotine constituents of tobacco smoke.

Design
Univariable MR and multivariable MR (MVMR) were used to measure the total and independent effects of genetic liability to NMR and CPD on major depressive disorder (MDD). Our primary method was inverse variance weighted (IVW) regression, with other methods as sensitivity analyses.

Setting and participants
For the exposures, we used genome-wide association study (GWAS) summary statistics among European ancestry individuals for CPD (n = 143 210) and NMR (n = 5185). For the outcome, a GWAS of MDD stratified by smoking status was conducted using individual-level data from UK Biobank (n = 35 871–194 881).

Measurements
Genetic variants associated with NMR (n = 6) and CPD (n = 53).

Findings
Univariable MR-IVW indicated a causal effect of CPD on MDD [odds ratio (OR) = 1.13, 95% confidence interval (CI) = 1.04–1.23, P = 0.003] but no clear evidence for an effect of NMR on MDD (OR = 0.98, 95% CI = 0.97–1.00, P = 0.134). MVMR indicated a causal effect of CPD on MDD when accounting for NMR (IVW: OR = 1.19, 95% CI = 1.03–1.37, P = 0.017; Egger: OR = 1.13, 95% CI = 0.89–1.43, P = 0.300) and weak evidence of a small effect of NMR on MDD when accounting for CPD (IVW: OR = 0.98, 95% CI = 0.96–1.00, P = 0.057; Egger: OR = 0.98, 95% CI = 0.96–1.00, P = 0.038).

Conclusions
The role of nicotine exposure in risk of depression cannot be entirely dismissed. However, the causal effect of tobacco smoking increasing depression risk appears to be largely independent of circulating nicotine exposure, which implies the role of alternative causal pathways.