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Disentangling the effects of nicotine versus non‐nicotine constituents of tobacco smoke on major depressive disorder: A multivariable Mendelian randomisation study.

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Title: Disentangling the effects of nicotine versus non‐nicotine constituents of tobacco smoke on major depressive disorder: A multivariable Mendelian randomisation study.
Authors: Burke, Chloe, Taylor, Gemma, Freeman, Tom P., Sallis, Hannah, Wootton, Robyn E., Munafò, Marcus R., Dardani, Christina, Khouja, Jasmine
Source: Addiction. Jun2025, Vol. 120 Issue 6, p1240-1252. 13p.
Subjects: Nicotine metabolism, Mental depression risk factors, Risk assessment, Research funding, Genome-wide association studies, Nicotine, Smoking, Mendelian randomization, Multivariate analysis, Descriptive statistics, Uk Biobank Ltd., Odds ratio, Statistics, Tobacco products, Confidence intervals, Regression analysis
Abstract: Background and aims: There is growing evidence that tobacco smoking causes depression, but it is unclear which constituents of tobacco smoke (e.g. nicotine, carbon monoxide) may be responsible. We used Mendelian randomisation (MR) to measure the independent effect of nicotine on depression, by adjusting the effect of circulating nicotine exposure [via nicotine metabolite ratio (NMR)] for the overall effect of smoking heaviness [via cigarettes per day (CPD)] to account for the non‐nicotine constituents of tobacco smoke. Design: Univariable MR and multivariable MR (MVMR) were used to measure the total and independent effects of genetic liability to NMR and CPD on major depressive disorder (MDD). Our primary method was inverse variance weighted (IVW) regression, with other methods as sensitivity analyses. Setting and participants: For the exposures, we used genome‐wide association study (GWAS) summary statistics among European ancestry individuals for CPD (n = 143 210) and NMR (n = 5185). For the outcome, a GWAS of MDD stratified by smoking status was conducted using individual‐level data from UK Biobank (n = 35 871–194 881). Measurements Genetic variants associated with NMR (n = 6) and CPD (n = 53). Findings Univariable MR‐IVW indicated a causal effect of CPD on MDD [odds ratio (OR) = 1.13, 95% confidence interval (CI) = 1.04–1.23, P = 0.003] but no clear evidence for an effect of NMR on MDD (OR = 0.98, 95% CI = 0.97–1.00, P = 0.134). MVMR indicated a causal effect of CPD on MDD when accounting for NMR (IVW: OR = 1.19, 95% CI = 1.03–1.37, P = 0.017; Egger: OR = 1.13, 95% CI = 0.89–1.43, P = 0.300) and weak evidence of a small effect of NMR on MDD when accounting for CPD (IVW: OR = 0.98, 95% CI = 0.96–1.00, P = 0.057; Egger: OR = 0.98, 95% CI = 0.96–1.00, P = 0.038). Conclusions: The role of nicotine exposure in risk of depression cannot be entirely dismissed. However, the causal effect of tobacco smoking increasing depression risk appears to be largely independent of circulating nicotine exposure, which implies the role of alternative causal pathways. [ABSTRACT FROM AUTHOR]
Copyright of Addiction is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Label: Title
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  Data: Disentangling the effects of nicotine versus non‐nicotine constituents of tobacco smoke on major depressive disorder: A multivariable Mendelian randomisation study.
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  Data: <searchLink fieldCode="AR" term="%22Burke%2C+Chloe%22">Burke, Chloe</searchLink><br /><searchLink fieldCode="AR" term="%22Taylor%2C+Gemma%22">Taylor, Gemma</searchLink><br /><searchLink fieldCode="AR" term="%22Freeman%2C+Tom+P%2E%22">Freeman, Tom P.</searchLink><br /><searchLink fieldCode="AR" term="%22Sallis%2C+Hannah%22">Sallis, Hannah</searchLink><br /><searchLink fieldCode="AR" term="%22Wootton%2C+Robyn+E%2E%22">Wootton, Robyn E.</searchLink><br /><searchLink fieldCode="AR" term="%22Munafò%2C+Marcus+R%2E%22">Munafò, Marcus R.</searchLink><br /><searchLink fieldCode="AR" term="%22Dardani%2C+Christina%22">Dardani, Christina</searchLink><br /><searchLink fieldCode="AR" term="%22Khouja%2C+Jasmine%22">Khouja, Jasmine</searchLink>
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  Data: <searchLink fieldCode="JN" term="%22Addiction%22">Addiction</searchLink>. Jun2025, Vol. 120 Issue 6, p1240-1252. 13p.
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  Data: <searchLink fieldCode="DE" term="%22Nicotine+metabolism%22">Nicotine metabolism</searchLink><br /><searchLink fieldCode="DE" term="%22Mental+depression+risk+factors%22">Mental depression risk factors</searchLink><br /><searchLink fieldCode="DE" term="%22Risk+assessment%22">Risk assessment</searchLink><br /><searchLink fieldCode="DE" term="%22Research+funding%22">Research funding</searchLink><br /><searchLink fieldCode="DE" term="%22Genome-wide+association+studies%22">Genome-wide association studies</searchLink><br /><searchLink fieldCode="DE" term="%22Nicotine%22">Nicotine</searchLink><br /><searchLink fieldCode="DE" term="%22Smoking%22">Smoking</searchLink><br /><searchLink fieldCode="DE" term="%22Mendelian+randomization%22">Mendelian randomization</searchLink><br /><searchLink fieldCode="DE" term="%22Multivariate+analysis%22">Multivariate analysis</searchLink><br /><searchLink fieldCode="DE" term="%22Descriptive+statistics%22">Descriptive statistics</searchLink><br /><searchLink fieldCode="DE" term="%22Uk+Biobank+Ltd%2E%22">Uk Biobank Ltd.</searchLink><br /><searchLink fieldCode="DE" term="%22Odds+ratio%22">Odds ratio</searchLink><br /><searchLink fieldCode="DE" term="%22Statistics%22">Statistics</searchLink><br /><searchLink fieldCode="DE" term="%22Tobacco+products%22">Tobacco products</searchLink><br /><searchLink fieldCode="DE" term="%22Confidence+intervals%22">Confidence intervals</searchLink><br /><searchLink fieldCode="DE" term="%22Regression+analysis%22">Regression analysis</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Background and aims: There is growing evidence that tobacco smoking causes depression, but it is unclear which constituents of tobacco smoke (e.g. nicotine, carbon monoxide) may be responsible. We used Mendelian randomisation (MR) to measure the independent effect of nicotine on depression, by adjusting the effect of circulating nicotine exposure [via nicotine metabolite ratio (NMR)] for the overall effect of smoking heaviness [via cigarettes per day (CPD)] to account for the non‐nicotine constituents of tobacco smoke. Design: Univariable MR and multivariable MR (MVMR) were used to measure the total and independent effects of genetic liability to NMR and CPD on major depressive disorder (MDD). Our primary method was inverse variance weighted (IVW) regression, with other methods as sensitivity analyses. Setting and participants: For the exposures, we used genome‐wide association study (GWAS) summary statistics among European ancestry individuals for CPD (n = 143 210) and NMR (n = 5185). For the outcome, a GWAS of MDD stratified by smoking status was conducted using individual‐level data from UK Biobank (n = 35 871–194 881). Measurements Genetic variants associated with NMR (n = 6) and CPD (n = 53). Findings Univariable MR‐IVW indicated a causal effect of CPD on MDD [odds ratio (OR) = 1.13, 95% confidence interval (CI) = 1.04–1.23, P = 0.003] but no clear evidence for an effect of NMR on MDD (OR = 0.98, 95% CI = 0.97–1.00, P = 0.134). MVMR indicated a causal effect of CPD on MDD when accounting for NMR (IVW: OR = 1.19, 95% CI = 1.03–1.37, P = 0.017; Egger: OR = 1.13, 95% CI = 0.89–1.43, P = 0.300) and weak evidence of a small effect of NMR on MDD when accounting for CPD (IVW: OR = 0.98, 95% CI = 0.96–1.00, P = 0.057; Egger: OR = 0.98, 95% CI = 0.96–1.00, P = 0.038). Conclusions: The role of nicotine exposure in risk of depression cannot be entirely dismissed. However, the causal effect of tobacco smoking increasing depression risk appears to be largely independent of circulating nicotine exposure, which implies the role of alternative causal pathways. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
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  Data: <i>Copyright of Addiction is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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    Identifiers:
      – Type: doi
        Value: 10.1111/add.70001
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      – Code: eng
        Text: English
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      Pagination:
        PageCount: 13
        StartPage: 1240
    Subjects:
      – SubjectFull: Nicotine metabolism
        Type: general
      – SubjectFull: Mental depression risk factors
        Type: general
      – SubjectFull: Risk assessment
        Type: general
      – SubjectFull: Research funding
        Type: general
      – SubjectFull: Genome-wide association studies
        Type: general
      – SubjectFull: Nicotine
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      – SubjectFull: Smoking
        Type: general
      – SubjectFull: Mendelian randomization
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      – SubjectFull: Multivariate analysis
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      – SubjectFull: Descriptive statistics
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      – SubjectFull: Uk Biobank Ltd.
        Type: general
      – SubjectFull: Odds ratio
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      – SubjectFull: Statistics
        Type: general
      – SubjectFull: Tobacco products
        Type: general
      – SubjectFull: Confidence intervals
        Type: general
      – SubjectFull: Regression analysis
        Type: general
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      – TitleFull: Disentangling the effects of nicotine versus non‐nicotine constituents of tobacco smoke on major depressive disorder: A multivariable Mendelian randomisation study.
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              M: 06
              Text: Jun2025
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              Y: 2025
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