Using Mendelian randomization to explore the gateway hypothesis: possible causal effects of smoking initiation and alcohol consumption on substance use outcomes

Zoe E Reed*, Robyn E Wootton, Marcus R Munafo

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

7 Citations (Scopus)
36 Downloads (Pure)


Background and Aims
Initial use of drugs such as tobacco and alcohol may lead to subsequent more problematic drug use—the ‘gateway’ hypothesis. However, observed associations may be due to a shared underlying risk factor, such as trait impulsivity. We used bidirectional Mendelian randomization (MR) to test the gateway hypothesis.

Our main method was inverse-variance weighted (IVW) MR, with other methods included as sensitivity analyses (where consistent results across methods would raise confidence in our primary results). MR is a genetic instrumental variable approach used to support stronger causal inference in observational studies.

Setting and participants
Genome-wide association summary data among European ancestry individuals for smoking initiation, alcoholic drinks per week, cannabis use and dependence, cocaine and opioid dependence (n = 1749–1 232 091).

Genetic variants for exposure.

We found evidence of causal effects from smoking initiation to increased drinks per week [(IVW): β = 0.06; 95% confidence interval (CI) = 0.03–0.09; P = 9.44 × 10−06], cannabis use [IVW: odds ratio (OR) = 1.34; 95% CI = 1.24–1.44; P = 1.95 × 10−14] and cannabis dependence (IVW: OR = 1.68; 95% CI = 1.12–2.51; P = 0.01). We also found evidence of an effect of cannabis use on the increased likelihood of smoking initiation (IVW: OR = 1.39; 95% CI = 1.08–1.80; P = 0.01). We did not find evidence of an effect of drinks per week on other substance use outcomes, except weak evidence of an effect on cannabis use (IVW: OR = 0.55; 95% CI = 0.16–1.93; P-value = 0.35). We found weak evidence of an effect of opioid dependence on increased drinks per week (IVW: β = 0.002; 95% CI = 0.0005–0.003; P = 8.61 × 10−03).

Bidirectional Mendelian randomization testing of the gateway hypothesis reveals that smoking initiation may lead to increased alcohol consumption, cannabis use and cannabis dependence. Cannabis use may also lead to smoking initiation and opioid dependence to alcohol consumption. However, given that tobacco and alcohol use typically begin before other drug use, these results may reflect a shared risk factor or a bidirectional effect for cannabis use and opioid dependence.
Original languageEnglish
Number of pages10
Early online date29 Sept 2021
Publication statusE-pub ahead of print - 29 Sept 2021

Bibliographical note

Funding Information:
This work was supported in part by Public Health England, the UK Medical Research Council Integrative Epidemiology Unit at the University of Bristol (Grant ref.: MC_UU_00011/7) and the National Institute for Health Research (NIHR) Biomedical Research Centre at the University Hospitals Bristol National Health Service Foundation Trust and the University of Bristol. The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research or the Department of Health. R.W. was supported by a postdoctoral fellowship from the South‐Eastern Regional Health Authority (2020024). We thank all the contributors to the consortia we have used GWAS results from in our analyses. We would also like to thank the research participants and employees of 23andMe for making this work possible.

Publisher Copyright:
© 2021 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.


  • Alcohol consumption
  • cannabis
  • gateway hypothesis
  • Mendelian randomization
  • smoking initiation
  • substance use


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