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.
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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.
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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 (2020). https://doi.org/10.1038/s41380-020-0785-6