Exploring the role of nicotine and smoking in sleep behaviours: A multi‐variable Mendelian randomisation study

BACKGROUND AND AIMS: Increased nicotine exposure (resulting from greater cigarette consumption and/or slower nicotine metabolism) may directly affect sleep and could underlie relationships between smoking and sleep behaviours identified previously. We conducted a Mendelian randomisation (MR) study to explore whether nicotine metabolism has a causal effect on sleep behaviours. DESIGN: Our main analysis method was inverse-variance weighted (IVW) Multivariable MR, which was used to examine the independent effects of nicotine metabolism and smoking heaviness on sleep behaviours. The model was developed to provide insights into the potential role of nicotine exposure. SETTING AND PARTICIPANTS: The genome-wide association summary data for these analyses were sourced from published genome-wide association study (GWAS) summary-level data, or GWAS conducted within the UK Biobank. Primary analyses focused on current smokers of European descent (N = 5185 to 487 153). MEASUREMENTS: We used genetic proxies of the nicotine metabolite ratio (NMR), cigarettes per day (CPD), and sleep behaviours (chronotype [being an "evening" person versus a "morning" person], ease of getting up in the morning, insomnia symptoms, napping, daytime sleepiness and sleep duration). RESULTS: Higher NMR (consistent with lower circulating nicotine levels per cigarette smoked) decreased the likelihood of being an "evening" person when accounting for CPD in current smokers [beta coefficient (β) = -0.04, 95% confidence interval (CI) -0.06 to -0.02, p < 0.001]. A higher NMR also increased the ease of getting up (β = 0.02, 95%CI 0.01 to 0.04, p = 0.001) and likelihood of napping (β = 0.02, 95%CI 0.01 to 0.03, p < 0.001) in current smokers. There was no consistent evidence for effects of NMR or CPD on insomnia symptoms or sleep duration, although increased sleep duration lowered NMR among current smokers (β = -0.43, 95%CI -0.74 to -0.12, p = 0.007), without corresponding effects on smoking heaviness. SUMMARY: Among current smokers, nicotine metabolism may play a direct role in the relationship between smoking and certain sleep behaviours, particularly those related to circadian preference and daytime alertness, independent of smoking heaviness. There is some evidence that sleep duration may influence nicotine metabolism.