Bidirectional effects between loneliness, smoking and alcohol use: evidence from a Mendelian randomization study

Background and Aims: Loneliness is associated with cigarette smoking and problematic alcohol use. Observational evidence suggests these associations arise because loneliness increases substance use; however, there is potential for reverse causation (problematic drinking damages social networks, leading to loneliness). With conventional epidemiological methods, controlling for (residual) confounding and reverse causality is difficult. This study applied Mendelian randomization (MR) to assess bidirectional causal effects among loneliness, smoking behaviour and alcohol (mis)use. MR uses genetic variants as instrumental variables to estimate the causal effect of an exposure on an outcome, if the assumptions are satisfied. Design: Our primary method was inverse-variance weighted (IVW) regression and the robustness of these findings was assessed with five different sensitivity methods. Setting: European ancestry. Participants: Summary-level data were drawn from the largest available independent genome-wide association studies (GWAS) of loneliness (n = 511 280), smoking (initiation (n = 249 171), cigarettes per day (n = 249 171) and cessation (n = 143 852), alcoholic drinks per week (n = 226 223) and alcohol dependence (n = 46 568). Measurements: Genetic variants predictive of the exposure variable were selected as instruments from the respective GWAS. Findings: There was weak evidence of increased loneliness leading to higher likelihood of initiating smoking, smoking more cigarettes, and a lower likelihood of quitting smoking. Additionally, there was evidence that initiating smoking increases loneliness [IVW, β = 0.30, 95% confidence interval (CI) = 0.22–0.38, P = 2.8 × 10−13]. We found no clear evidence for a causal effect of loneliness on drinks per week (IVW, β = 0.01, 95% CI = −0.11, 0.13, P = 0.865) or alcohol dependence (IVW, β = 0.09, 95% CI = −0.19, 0.36, P = 0.533) nor of alcohol use on loneliness (drinks per week IVW, β = 0.09, 95% CI = −0.02, 0.22, P = 0.076; alcohol dependence IVW, β = 0.06, 95% CI = −0.02, 0.13, P = 0.162). Conclusions: There appears to be tentative evidence for causal, bidirectional, increasing effects between loneliness and cigarette smoking, especially for smoking initiation increasing loneliness.