Evidence for causal effects of lifetime smoking on risk for depression and schizophrenia: a Mendelian randomisation study
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Abstract
Background: Smoking prevalence is higher amongst individuals with schizophrenia and depression compared with the general population. Mendelian randomisation (MR) can examine whether this association is causal using genetic variants identified in genome-wide association studies (GWAS). Methods: We conducted two-sample MR to explore the bi-directional effects of smoking on schizophrenia and depression. For smoking behaviour, we used (1) smoking initiation GWAS from the GSCAN consortium and (2) we conducted our own GWAS of lifetime smoking behaviour (which captures smoking duration, heaviness and cessation) in a sample of 462690 individuals from the UK Biobank. We validated this instrument using positive control outcomes (e.g. lung cancer). For schizophrenia and depression we used GWAS from the PGC consortium. Results: There was strong evidence to suggest smoking is a risk factor for both schizophrenia (odds ratio (OR) 2.27, 95% confidence interval (CI) 1.67–3.08, p < 0.001) and depression (OR 1.99, 95% CI 1.71–2.32, p < 0.001). Results were consistent across both lifetime smoking and smoking initiation. We found some evidence that genetic liability to depression increases smoking ( β = 0.091, 95% CI 0.027–0.155, p = 0.005) but evidence was mixed for schizophrenia ( β = 0.022, 95% CI 0.005–0.038, p = 0.009) with very weak evidence for an effect on smoking initiation. Conclusions: These findings suggest that the association between smoking, schizophrenia and depression is due, at least in part, to a causal effect of smoking, providing further evidence for the detrimental consequences of smoking on mental health.
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Recent work has suggested a potentially genetic causal link between chronotype and odds of developing depressive symptoms, and similar findings have been reported for smoking or alcohol abuse and depression.
“For example, recent work has suggested that there is a potentially genetic causal link between chronotype and odds of developing depressive symptoms [38] and similar findings have been reported for smoking [39] or alcohol abuse [40] and depression.”
From Neandertal introgression partitions the genetic landscape of neuropsychiatric disorders and associated behavioral phenotypes (2022) · cites this paper as [39]
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“For example, recent work has suggested that there is a potentially genetic causal link between chronotype and odds of developing depressive symptoms [38] and similar findings have been reported for smoking [39] or alcohol abuse [40] and depression.”
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- Authors
- Wootton, R. E., Richmond, R. C., Stuijfzand, B. G., Lawn, R. B., Sallis, H. M., Taylor, G. M. J., Hemani, G., Jones, H. J., Zammit, S., Davey Smith, G., & Munafò, M. R.
- Affiliations
- University Hospitals Bristol NHS Foundation Trust (GB)
- University of Bristol (GB)
- University of Bath (GB)
- Corresponding author
- Wootton, Robyn E.
- ORCID
- Venue
- Psychological Medicine
- Publisher
- Cambridge University Press (CUP)
- Published
- 2019-11-06
- Volume
- 50
- Issue
- 14
- Pages
- 2435-2443
- ISSN
- 0033-2917 (ISSN-L)
- 1469-8978
- PMC
- PMC7610182
- OpenAlex
- W2972751683
- Cited by
- 587
- References
- 65
- Citations by year
- 2026: 48 · 2025: 98 · 2024: 122 · 2023: 106 · 2022: 75 · 2021: 72 · 2020: 47 · 2019: 14 · 2018: 5
- FWCI
- 35.65
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Psychological Medicine (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion, cc-by)
- Bristol Research (University of Bristol) (submittedVersion, other-oa)
- Explore Bristol Research (submittedVersion)
- Funders
- Wellcome Trust (MC_UU_00011/1, 102215/2/13/2), 208806, MC_UU_00011/5, Z/17/Z, 217065/Z/19/Z, 102215, 208806/Z/17/Z, 102215/2/13/, BB/I025751/1, C18281/A19169, BB/I025263/1)
- University Hospitals Bristol NHS Foundation Trust
- Cancer Research UK (C18281/, C56067/A21330, 102215/2/13/2, BB/I025263/1, C18281 / A19169, MC_UU_00011/1, A21330, A19169, BB/I025751/1, 19169, MC_UU_00011/5)
- National Institute for Health and Care Research (C18281/A19169, BB/I025263/1, MC_UU_00011/5, BB/I025751/1, MC_UU_00011/1)
- Department of Health and Social Care
- University of Bristol (MC_UU_00011/7, C18281/A19169, MC‐UU‐00011‐5, MC_UU_00011/1, 102215/2/13/2, BB/I025751/1, BB/I025263/1)
- Directorate for Biological Sciences
- Medical Research Council (102215, MC_UU_00011/7, ref: 102215/2/13/2, MC_UU_00011/1, MC_UU_00011/5, MR/M006727/1, MC_UU_00011/5, 102215/2/13/2, MC_PC_17228, MR/L010305/1, MC_PC_15018, MC_UU_00011/1, ES/N000498/1, MC_PC_19009, MC_UU_00011)
- Biotechnology and Biological Sciences Research Council (BB/I025263/1, BB/I025751/1)
- Economic and Social Research Council (MC_UU_00011/1, ES/N000498/1, MC_UU_00011/5, 102215/2/13/2)
- Topics
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- smoking, lifetime smoking, smoking initiation, schizophrenia, depression, causal effects, genetic susceptibility, lung cancer, mental health, smoking cessation
- MeSH terms
- Depression, Female, United Kingdom, Humans, Male, Middle Aged, Risk Factors, Schizophrenia, Smoking, Causality, Biological Specimen Banks, White People, Genome-Wide Association Study, Mendelian Randomization Analysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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