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

Br J Psychiatry. 2021 Feb;218(2):88-94. doi: 10.1192/bjp.2019.202.


Background: There 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.

Aims: We conducted a bidirectional Mendelian randomisation (MR) study to investigate the direction and evidence for a causal nature of the relationship between smoking and bipolar disorder.

Method: We used publicly 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 analytical methods with different, orthogonal assumptions to triangulate results, including inverse-variance weighted (IVW), MR-Egger, MR-Egger SIMEX, weighted-median, weighted-mode and Steiger-filtered analyses.

Results: Across 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 = 1.44 × 10-8, lifetime smoking ORIVW = 1.72, 95% CI 1.29-2.28, P = 1.8 × 10-4). The MR analyses of the effect of liability to bipolar disorder on smoking provided no clear evidence of a strong causal effect (smoking heaviness betaIVW = 0.028, 95% CI 0.003-0.053, P = 2.9 × 10-2).

Conclusions: These 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 bipolar disorder 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.

Keywords: Mendelian randomisation; Smoking; bipolar affective disorders; environmental; risk factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bipolar Disorder* / etiology
  • Bipolar Disorder* / genetics
  • Genome-Wide Association Study
  • Humans
  • Mendelian Randomization Analysis
  • Polymorphism, Single Nucleotide
  • Smoking
  • Smoking Cessation*