Exploring causality of the association between smoking and Parkinson's disease

Valentina Gallo, Paolo Vineis, Mariagrazia Cancellieri, Paolo Chiodini, Roger A Barker, Carol Brayne, Neil Pearce, Roel Vermeulen, Salvatore Panico, Bas Bueno-de-Mesquita, Nicola Vanacore, Lars Forsgren, Silvia Ramat, Eva Ardanaz, Larraitz Arriola, Jesper Peterson, Oskar Hansson, Diana Gavrila, Carlotta Sacerdote, Sabina SieriTilman Kühn, Verena A Katzke, Yvonne T van der Schouw, Andreas Kyrozis, Giovanna Masala, Amalia Mattiello, Robert Perneczky, Lefkos Middleton, Rodolfo Saracci, Elio Riboli

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BACKGROUND: The aim of this paper is to investigate the causality of the inverse association between cigarette smoking and Parkinson's disease (PD). The main suggested alternatives include a delaying effect of smoking, reverse causality or an unmeasured confounding related to a low-risk-taking personality trait.

METHODS: A total of 715 incident PD cases were ascertained in a cohort of 220 494 individuals from NeuroEPIC4PD, a prospective European population-based cohort study including 13 centres in eight countries. Smoking habits were recorded at recruitment. We analysed smoking status, duration, and intensity and exposure to passive smoking in relation to PD onset.

RESULTS: Former smokers had a 20% decreased risk and current smokers a halved risk of developing PD compared with never smokers. Strong dose-response relationships with smoking intensity and duration were found. Hazard ratios (HRs) for smoking <20 years were 0.84 [95% confidence interval (CI) 0.67-1.07], 20-29 years 0.73 (95% CI 0.56-0.96) and >30 years 0.54 (95% CI 0.43-0.36) compared with never smokers. The proportional hazard assumption was verified, showing no change of risk over time, arguing against a delaying effect. Reverse causality was disproved by the consistency of dose-response relationships among former and current smokers. The inverse association between passive smoking and PD, HR 0.70 (95% CI 0.49-0.99) ruled out the effect of unmeasured confounding.

CONCLUSIONS: These results are highly suggestive of a true causal link between smoking and PD, although it is not clear which is the chemical compound in cigarette smoking responsible for the biological effect.

Original languageEnglish
Pages (from-to)912-925
Number of pages14
JournalInternational Journal of Epidemiology
Issue number3
Early online date20 Nov 2018
Publication statusPublished - 01 Jun 2019

Bibliographical note

© The Author(s) 2018. Published by Oxford University Press on behalf of the International Epidemiological Association.


  • Aged
  • Causality
  • Cigarette Smoking/epidemiology
  • Female
  • Humans
  • Male
  • Middle Aged
  • Parkinson Disease/epidemiology
  • Proportional Hazards Models
  • Protective Factors
  • Time Factors
  • Tobacco Smoke Pollution/statistics & numerical data

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  • Cite this

    Gallo, V., Vineis, P., Cancellieri, M., Chiodini, P., Barker, R. A., Brayne, C., Pearce, N., Vermeulen, R., Panico, S., Bueno-de-Mesquita, B., Vanacore, N., Forsgren, L., Ramat, S., Ardanaz, E., Arriola, L., Peterson, J., Hansson, O., Gavrila, D., Sacerdote, C., ... Riboli, E. (2019). Exploring causality of the association between smoking and Parkinson's disease. International Journal of Epidemiology, 48(3), 912-925. https://doi.org/10.1093/ije/dyy230