Abstract
Use of substances such as cannabis, alcohol, and tobacco, has been associated with increased risk of suicide attempt in several observational studies. However, establishing whether these associations are causal is challenging when using observational designs. To evaluate the potential causal contributions of cannabis use, alcohol use, and tobacco smoking to suicide attempt, we applied two-sample Mendelian randomization, an instrumental variable approach using single-nucleotide polymorphisms (SNPs) as instrumental variables for three exposures: lifetime cannabis use (yes/no; 42 instrument SNPs; GWAS sample size [N] = 162,082), alcohol use (drinks-per-week; 53 instrument SNPs; N = 941,280), and tobacco smoking (initiation, yes/no; 156 instrument SNPs; N = 1,232,091; heaviness; 27 instrument SNPs; N = 337,334). The main outcome was suicide attempt measured from hospital records (N = 50,264). All data come from publicly available summary statistics of genome-wide association studies of participants of European ancestry. We found evidence supporting a possible causal role of cannabis (OR = 1.18; 95% CI = 1.01–1.37, P = 0.032), alcohol (OR = 1.95; 95% CI = 1.15–3.32, P = 0.013), and smoking (initiation, OR = 1.90; 95% CI = 1.54–2.34, P < 0.001; heaviness, OR = 2.13; 95% CI = 1.13–3.99; P = 0.019) on suicide attempt. Using multivariable Mendelian randomization, we found that only cannabis showed a direct pathway to suicide attempt (P = 0.001), suggesting that the effect of alcohol and smoking was mediated by the other substance use phenotypes. No evidence was found for reverse causation, i.e., associations of suicide attempt on cannabis (P = 0.483), alcohol (P = 0.234), smoking initiation (P = 0.144), and heaviness (P = 0.601). In conclusion, evidence from this quasi-experimental study based on genetic data from large-scale GWASs are consistent with a causal role of cannabis, alcohol, and tobacco smoking on suicide attempt.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Turecki G, Brent DA. Suicide and suicidal behaviour. Lancet. 2016;387:1227–39.
WHO. WHO | Suicide data. WHO. 2015. http://www.who.int/mental_health/prevention/suicide/suicideprevent/en/. Accessed 24 Feb 2018.
Nock MK, Green JG, Hwang I, McLaughlin KA, Sampson NA, Zaslavsky AM, et al. Prevalence, correlates, and treatment of lifetime suicidal behavior among adolescents: results from the National Comorbidity Survey Replication Adolescent Supplement. JAMA Psychiatry. 2013;70:300–10.
Goldman-Mellor SJ, Caspi A, Harrington H, Hogan S, Nada-Raja S, Poulton R, et al. Suicide attempt in young people: a signal for long-term health care and social needs. JAMA Psychiatry. 2014;71:119–27.
GBD 2016 Alcohol and Drug Use Collaborators. The global burden of disease attributable to alcohol and drug use in 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Psychiatry. 2018;5:987–1012.
Berlin I, Hakes JK, Hu M-C, Covey LS. Tobacco use and suicide attempt: longitudinal analysis with retrospective reports. PLOS ONE. 2015;10:e0122607.
Chang HB, Munroe S, Gray K, Porta G, Douaihy A, Marsland A, et al. The role of substance use, smoking, and inflammation in risk for suicidal behavior. J Affect Disord. 2019;243:33–41.
Darvishi N, Farhadi M, Haghtalab T, Poorolajal J. Alcohol-related risk of suicidal ideation, suicide attempt, and completed suicide: a meta-analysis. PLoS ONE. 2015;10:e0126870.
Flensborg-Madsen T, Knop J, Mortensen EL, Becker U, Sher L, Grønbæk M. Alcohol use disorders increase the risk of completed suicide—irrespective of other psychiatric disorders. A longitudinal cohort study. Psychiatry Res. 2009;167:123–30.
Gobbi G, Atkin T, Zytynski T, Wang S, Askari S, Boruff J, et al. Association of Cannabis use in adolescence and risk of depression, anxiety, and suicidality in young adulthood: a systematic review and meta-analysis. JAMA Psychiatry. 2019;76:426–34.
Korhonen T, Sihvola E, Latvala A, Dick DM, Pulkkinen L, Nurnberger J, et al. Early-onset tobacco use and suicide-related behavior—a prospective study from adolescence to young adulthood. Addict Behav. 2018;79:32–8.
Li D, Yang X, Ge Z, Hao Y, Wang Q, Liu F, et al. Cigarette smoking and risk of completed suicide: a meta-analysis of prospective cohort studies. J Psychiatr Res. 2012;46:1257–66.
Malone KM, Waternaux C, Haas GL, Cooper TB, Li S, Mann JJ. Cigarette smoking, suicidal behavior, and serotonin function in major psychiatric disorders. Am J Psychiatry. 2003;160:773–9.
Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007;370:319–28.
Pingault J-B, O’Reilly PF, Schoeler T, Ploubidis GB, Rijsdijk F, Dudbridge F. Using genetic data to strengthen causal inference in observational research. Nat Rev Genet. 2018;19:566–80.
Gilbert R, Widom CS, Browne K, Fergusson D, Webb E, Janson S. Burden and consequences of child maltreatment in high-income countries. Lancet. 2009;373:68–81.
Fergusson DM, Horwood LJ, Ridder EM, Beautrais AL. Suicidal behaviour in adolescence and subsequent mental health outcomes in young adulthood. Psychol Med. 2005;35:983–93.
Marschall-Lévesque S, Castellanos-Ryan N, Parent S, Renaud J, Vitaro F, Boivin M, et al. Victimization, suicidal ideation, and alcohol use from age 13 to 15 years: support for the self-medication model. J Adolesc Health. 2017;60:380–7.
Steinhausen H-C, Bösiger R, Metzke CW. Stability, correlates, and outcome of adolescent suicidal risk. J Child Psychol Psychiatry. 2006;47:713–22.
Glass TA, Goodman SN, Hernán MA, Samet JM. Causal inference in public health. Annu Rev Public Health. 2013;34:61–75.
Burgess S, Scott RA, Timpson NJ, Davey Smith G, Thompson SG. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol. 2015;30:543–52.
Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018;362:k601.
Erlangsen A, Appadurai V, Wang Y, Turecki G, Mors O, Werge T, et al. Genetics of suicide attempts in individuals with and without mental disorders: a population-based genome-wide association study. Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-018-0218-y.
Pasman JA, Verweij KJH, Gerring Z, Stringer S, Sanchez-Roige S, Treur JL, et al. GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia. Nat Neurosci. 2018;21:1161.
Liu M, Jiang Y, Wedow R, Li Y, Brazel DM, Chen F, et al. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat Genet. 2019;51:237.
Wootton RE, Lawn RB, Millard LAC, Davies NM, Taylor AE, Munafò MR, et al. Evaluation of the causal effects between subjective wellbeing and cardiometabolic health: mendelian randomisation study. BMJ. 2018;362:k3788.
Choi KW, Chen C-Y, Stein MB, Klimentidis YC, Wang M-J, Koenen KC, et al. Assessment of bidirectional relationships between physical activity and depression among adults: A 2-Sample Mendelian Randomization Study. JAMA Psychiatry. 2019. https://doi.org/10.1001/jamapsychiatry.2018.4175.
Burgess S, Thompson SG. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol. 2011;40:755–64.
Zhao Q, Wang J, Hemani G, Bowden J, Small DS. Statistical inference in two-sample summary-data Mendelian randomization using robust adjusted profile score. Math Stat. 2018. arXiv:180109652.
Burgess S, Thompson SG. Multivariable Mendelian Randomization: the use of pleiotropic genetic variants to estimate causal effects. Am J Epidemiol. 2015;181:251–60.
Sanderson E, Davey Smith G, Windmeijer F, Bowden J. An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings. Int J Epidemiol. 2018. https://doi.org/10.1093/ije/dyy262.
Hemani G, Zheng J, Elsworth B, Wade KH, Haberland V, Baird D, et al. The MR-Base platform supports systematic causal inference across the human phenome. ELife. 2018;7:e34408.
Yavorska OO, Burgess S. Mendelian randomization: an R package for performing Mendelian randomization analyses using summarized data. Int J Epidemiol. 2017;46:1734–9.
Borges G, Bagge CL, Orozco R. A literature review and meta-analyses of cannabis use and suicidality. J Affect Disord. 2016;195:63–74.
Agrawal A, Nelson EC, Bucholz KK, Tillman R, Grucza RA, Statham DJ, et al. Major depressive disorder, suicidal thoughts and behaviours, and cannabis involvement in discordant twins: a retrospective cohort study. Lancet Psychiatry. 2017;4:706–14.
Lynskey MT, Glowinski AL, Todorov AA, Bucholz KK, Madden PAF, Nelson EC, et al. Major depressive disorder, suicidal ideation, and suicide attempt intwins discordant for cannabis dependence and early-onset cannabis use. Arch Gen Psychiatry. 2004;61:1026–32.
Staff J, Schulenberg JE, Maslowsky J, Bachman JG, O’Malley PM, Maggs JL, et al. Substance use changes and social role transitions: proximal developmental effects on ongoing trajectories from late adolescence through early adulthood. Dev Psychopathol. 2010;22:917–32.
Kendler KS, Neale MC, MacLean CJ, Heath AC, Eaves LJ, Kessler RC. Smoking and major depression. A causal analysis. Arch Gen Psychiatry. 1993;50:36–43.
Kendler KS, Lönn SL, Sundquist J, Sundquist K. Smoking and schizophrenia in population cohorts of Swedish women and men: a prospective co-relative control study. Am J Psychiatry. 2015;172:1092–1100.
Fergusson DM, Boden JM, Horwood LJ. Tests of causal links between alcohol abuse or dependence and major depression. Arch Gen Psychiatry. 2009;66:260–6.
Pompili M, Serafini G, Innamorati M, Dominici G, Ferracuti S, Kotzalidis GD, et al. Suicidal behavior and alcohol abuse. Int J Environ Res Public Health. 2010;7:1392–431.
Green M, Turner S, Sareen J. Smoking and suicide: biological and social evidence and causal mechanisms. J Epidemiol Community Health. 2017;71:839–40.
Vinod KY, Hungund BL. Role of the endocannabinoid system in depression and suicide. Trends Pharmacol Sci. 2006;27:539–45.
Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol. 2015;44:512–25.
Bowden J, Del Greco MF, Minelli C, Davey Smith G, Sheehan NA, Thompson JR. Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I2 statistic. Int J Epidemiol. 2016;45:1961–74.
Acknowledgements
MO is funded by the European Union’s Horizon 2020 research and innovation program (grant agreement no. 793396). GT holds a Canada Research Chair (Tier 1) and a NARSAD Distinguished Investigator Award, and is supported by grants from the Canadian Institute of Health Research (CIHR) (FDN148374 and EGM141899). MCG, JRS, and GT are supported by the Fonds de recherche du Québec—Santé (FRQS) through the Quebec Network on Suicide, Mood Disorders and Related Disorders. MCG receives funding from the American Foundation for Suicide Prevention and holds a Canada Research Chair (Tier 2). NCR and MCG are fellows of the Fonds de Recherche en Santé du Québec. NCR and JRS are supported by grants from the CIHR (PJT-148551) and a CIHR-Canadian Center on Substance Use and Addiction Catalyst Grant. JRS is also supported by the Fond Monique Gaumond pour la recherche sur les maladies affectives. RET is funded by the Social Sciences and Humanities Research Council of Canada. Funders have no role in study design, data analysis, interpretation of the data, writing of the paper.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Orri, M., Séguin, J.R., Castellanos-Ryan, N. et al. A genetically informed study on the association of cannabis, alcohol, and tobacco smoking with suicide attempt. Mol Psychiatry 26, 5061–5070 (2021). https://doi.org/10.1038/s41380-020-0785-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41380-020-0785-6
This article is cited by
-
Estimating the direct effects of the genetic liabilities to bipolar disorder, schizophrenia, and behavioral traits on suicide attempt using a multivariable Mendelian randomization approach
Neuropsychopharmacology (2024)
-
Association of chronic pain with suicide attempt and death by suicide: a two-sample Mendelian randomization
Molecular Psychiatry (2024)
-
Comparison of the rate of certain trace metals accumulation in indoor plants for smoking and non-smoking areas
Environmental Science and Pollution Research (2023)
-
The genetic aetiology of cannabis use: from twin models to genome-wide association studies and beyond
Translational Psychiatry (2022)
-
Cannabis and Intentional Self-injury: a Narrative Review
Current Addiction Reports (2022)