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

Published online by Cambridge University Press:  17 September 2019

Jentien M. Vermeulen
Medical Doctor, Department of Psychiatry, Amsterdam UMC, University of Amsterdam, The Netherlands
Robyn E. Wootton
Post-doc Researcher, School of Psychological Science, University of Bristol; MRC Integrative Epidemiology Unit, University of Bristol; and NIHR Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and the University of Bristol, UK
Jorien L. Treur
Post-doc Researcher, Department of Psychiatry, Amsterdam UMC, University of Amsterdam, The Netherlands
Hannah M. Sallis
Post-doc Researcher, School of Psychological Science, University of Bristol; and MRC Integrative Epidemiology Unit, University of Bristol, UK
Hannah J. Jones
Post-doc Researcher, Department of Population Health Sciences, Bristol Medical School, University of Bristol; and MRC Integrative Epidemiology Unit, University of Bristol, UK
Stanley Zammit
Professor of Psychiatric Epidemiology, Department of Population Health Sciences, Bristol Medical School, University of Bristol, UK; and MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, University of Cardiff, UK
Wim van den Brink
Emeritus Professor of Addiction, Department of Psychiatry, Amsterdam UMC, University of Amsterdam, The Netherlands
Guy M. Goodwin
Professor of Psychiatry, Department of Psychiatry, University of Oxford; and Oxford Health NHS Foundation Trust, Oxford, UK
Lieuwe de Haan
Professor of Psychotic Disorders, Department of Psychiatry, Amsterdam UMC, University of Amsterdam, The Netherlands
Marcus R. Munafò
Professor of Biological Psychology, School of Psychological Science, University of Bristol, Bristol; MRC Integrative Epidemiology Unit, University of Bristol; and UK Centre for Tobacco and Alcohol Studies, University of Bristol, UK



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.

Copyright © The Royal College of Psychiatrists 2019

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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.


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