Investigating causality in associations between smoking initiation and schizophrenia using Mendelian randomization
Open accessAbstract
Smoking is strongly associated with schizophrenia. Although it has been widely assumed that this reflects self-medication, recent studies suggest that smoking may be a risk factor for schizophrenia. We performed two-sample bi-directional Mendelian randomization using summary level genomewide association data from the Tobacco And Genetics Consortium and Psychiatric Genomics Consortium. Variants associated with smoking initiation and schizophrenia were combined using an inverse-variance weighted fixed-effects approach. We found evidence consistent with a causal effect of smoking initiation on schizophrenia risk (OR 1.73, 95% CI 1.30–2.25, p < 0.001). However, after relaxing the p-value threshold to include variants from more than one gene and minimize the potential impact of pleiotropy, the association was attenuated (OR 1.03, 95% CI 0.97–1.09, p = 0.32). There was little evidence in support of a causal effect of schizophrenia on smoking initiation (OR 1.01, 95% CI 0.98–1.04, p = 0.32). MR Egger regression sensitivity analysis indicated no evidence for pleiotropy in the effect of schizophrenia on smoking initiation (intercept OR 1.01, 95% CI 0.99–1.02, p = 0.49). Our findings provide little evidence of a causal association between smoking initiation and schizophrenia, in either direction. However, we cannot rule out a causal effect of smoking on schizophrenia related to heavier, lifetime exposure, rather than initiation.
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No consistent evidence for causal relations between smoking initiation and schizophrenia diagnosis in either direction.
“They found no consistent evidence for causal relations between initiation of smoking and schizophrenia diagnosis, in either direction.”
From A meta-review of "lifestyle psychiatry": the role of exercise, smoking, diet and sleep in the prevention and treatment of mental disorders (2020) · cites this paper as [55]
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- Authors
- Gage, S. H., Jones, H. J., Taylor, A. E., Burgess, S., Zammit, S., & Munafò, M. R.
- Affiliations
- University of Bristol (GB)
- University of Cambridge (GB)
- Corresponding author
- Gage, Suzanne H.
- Venue
- Scientific Reports
- Published
- 2017-01-19
- Volume
- 7
- Issue
- 1
- Pages
- 40653-40653
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5244403
- OpenAlex
- W2577945917
- Cited by
- 57
- References
- 35
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 5 · 2023: 3 · 2022: 4 · 2021: 8 · 2020: 11 · 2019: 10 · 2018: 11 · 2017: 2
- FWCI
- 6.11
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion, cc-by)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Explore Bristol Research (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Wellcome Trust (204623/Z/16/Z, 100114, 100114/Z/12/Z)
- United Kingdom Clinical Research Collaboration
- Cancer Research UK (100114)
- National Institute for Health and Care Research (NF-SI-0512-10165)
- British Heart Foundation (MR/M006727/1, RG/08/014/24067)
- Medical Research Council (MC_UU_12013, MC_UU_12013/6, MR/M006727/1, MR/L003120/1)
- Economic and Social Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- smoking initiation, schizophrenia, causal inference, self-medication, bidirectional Mendelian randomization, pleiotropy, schizophrenia risk factors
- MeSH terms
- Disease Susceptibility, Female, Humans, Male, Phenotype, Risk Factors, Schizophrenia, Smoking, Genetic Variation, Odds Ratio, Risk Assessment, Genome-Wide Association Study, Mendelian Randomization Analysis
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