Smoking and the risk for bipolar disorder: causal evidence from a bidirectional Mendelian randomization study

Abstract

ImportanceThere is increasing evidence that smoking is a risk factor for severe mental illness, including bipolar disorder. Conversely, patients with bipolar disorder might smoke more (often) as a result of the psychiatric disorder. Research that investigates causality and the direction of the relationship between smoking and bipolar disorder has been lacking.\n\nObjectiveTo investigate the direction and causal nature of the relationship between smoking and bipolar disorder we conducted a bidirectional Mendelian randomization (MR) study.\n\nData sourcesPublicly available summary statistics from genome-wide association studies on bipolar disorder, smoking initiation, smoking heaviness, smoking cessation and lifetime smoking (i.e., a compound measure of heaviness, duration and cessation). We applied multiple analytical methods with different, orthogonal assumptions to triangulate results, including inverse-variance weighted (IVW), MR-Egger or Egger SIMEX, weighted median, weighted mode, and Steiger filtered analyses.\n\nResultsAcross different methods of MR, consistent evidence was found for a positive effect of smoking on the odds of bipolar disorder (smoking initiation ORIVW=1.46, 95% CI=1.28-1.66, P=1.44x10-8, lifetime smoking ORIVW=1.72, 95% CI=1.29-2.28, P=1.8x10-4). The MR analyses of the liability of bipolar disorder on smoking provided no clear evidence of a strong causal effect (smoking initiation betaIVW= -0.008, 95% CI= -0.026-0.009, P=0.35; P=0.94; smoking heaviness betaIVW=0.028, 95% CI= 0.003-0.053, P=2.9x10-2; smoking cessation ORIVW= 0.997, 95% CI= 0.981-1.014, P=0.74; lifetime smoking betaIVW= -0.001, 95%CI=-0.022-0.020, P=0.95).\n\nConclusionsThese findings suggest that smoking initiation and lifetime smoking are likely to be a causal risk factor for developing bipolar disorder. We found some evidence that liability to smoking increased smoking heaviness. Given that smoking is a modifiable risk factor, these findings further support investment into smoking prevention and treatment in order to reduce mental health problems in future generations.