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

  • Jentien M. Vermeulen (a1), Robyn E. Wootton (a2), Jorien L. Treur (a3), Hannah M. Sallis (a4), Hannah J. Jones (a5), Stanley Zammit (a6), Wim van den Brink (a7), Guy M. Goodwin (a8), Lieuwe de Haan (a9) and Marcus R. Munafò (a10)...



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.


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.


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.


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).


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.

Declaration of interest

W.v.d.B received fees in the past 3 years from Indivior, C&A Pharma, Opiant and Angelini. G.M.G. is a National Institute for Health Research (NIHR) Emeritus Senior Investigator, holds shares in P1vital and has served as consultant, advisor or CME speaker in the past 3 years for Allergan, Angelini, Compass Pathways, MSD, Lundbeck (/Otsuka and /Takeda), Medscape, Minervra, P1Vital, Pfizer, Sage, Servier, Shire and Sun Pharma.


Corresponding author

Correspondence: Jentien Vermeulen, Amsterdam UMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. Email:


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

  • Jentien M. Vermeulen (a1), Robyn E. Wootton (a2), Jorien L. Treur (a3), Hannah M. Sallis (a4), Hannah J. Jones (a5), Stanley Zammit (a6), Wim van den Brink (a7), Guy M. Goodwin (a8), Lieuwe de Haan (a9) and Marcus R. Munafò (a10)...
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