Article open access publication

Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis: the CARTA consortium

BMJ Open, BMJ, ISSN 2044-6055

Volume 4, 10, 2014

DOI:10.1136/bmjopen-2014-006141, Dimensions: pub.1038296275, PMC: PMC4187451, PMID: 25293386,



  1. (1) University of Bristol, grid.5337.2
  2. (2) St Olav's University Hospital, grid.52522.32
  3. (3) Norwegian University of Science and Technology, grid.5947.f
  4. (4) University of Queensland, grid.1003.2
  5. (5) University of Edinburgh, grid.4305.2
  6. (6) University College London, grid.83440.3b
  7. (7) Erasmus University Medical Center, grid.5645.2
  8. (8) University of Helsinki, grid.7737.4
  9. (9) Hospital District of North Karelia, Joensuu, Finland.
  10. (10) National Institute for Health and Welfare, grid.14758.3f
  11. (11) University of Eastern Finland, grid.9668.1
  12. (12) University of Oulu, grid.10858.34
  13. (13) South West London and St George's Mental Health Trust, London, UK.
  14. (14) Research Centre for Prevention and Health, the Capital Region of Denmark, Denmark.
  15. (15) Gentofte Hospital, grid.411646.0, Capital Region
  16. (16) University of Copenhagen, grid.5254.6, KU
  17. (17) VU Amsterdam, grid.12380.38
  18. (18) University Hospital of Lausanne, grid.8515.9
  19. (19) London School of Hygiene & Tropical Medicine, grid.8991.9
  20. (20) Folkhälsans Forskningscentrum, grid.428673.c
  21. (21) Broad Institute, grid.66859.34
  22. (22) Wellcome Sanger Institute, grid.10306.34
  23. (23) MRC Unit for Lifelong Health, Ageing at UCL, UK.
  24. (24) University of Toronto, grid.17063.33
  25. (25) University of Otago, grid.29980.3a
  26. (26) University of Oxford, grid.4991.5
  27. (27) Hospital for Sick Children, grid.42327.30
  28. (28) University of Southern Denmark, grid.10825.3e, SDU
  29. (29) Helsinki University Central Hospital, grid.15485.3d
  30. (30) Vaasa Central Hospital, grid.417201.1
  31. (31) Rigshospitalet, grid.475435.4, Capital Region
  32. (32) South Australian Health and Medical Research Institute, grid.430453.5
  33. (33) University of South Australia, grid.1026.5
  34. (34) Oulu University Hospital, grid.412326.0
  35. (35) Imperial College London, grid.7445.2


OBJECTIVES: To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach. DESIGN: Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress. PARTICIPANTS: Current, former and never smokers of European ancestry aged ≥16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). PRIMARY OUTCOME MEASURES: Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis. RESULTS: The analytic sample included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers. CONCLUSIONS: Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.


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