Using large summary-level GWAS data and complementary two-sample MR methods, we show that the genetic liability for tobacco smoking has potential causal relationships with several respiratory infection and disease outcomes, including COVID-19. These tobacco smoking-respiratory findings were supported by multivariable MR analyses accounting for alcohol and cannabis use and abuse, which in addition the broadly consistent IVW results (within the IVW MR 95% confidence interval but typically less precise) with estimates from the weighted median, weighted mode, and MR Egger sensitivity analyses strengthens causal inference. Further, in single variable MR, we identify potential adverse impact CUD on lower respiratory infection, the common cold, and several asthma-related infections, suggesting evidence for a dose-dependent impact of cannabis use where heavy cannabis use may be harmful to the respiratory system. In parallel, we find little evidence for an alcohol-respiratory infection relationship suggesting that previous observational data may be due to confounding.

Our COVID-19 results extend recent MR studies showing adverse effects of smoking on COVID-19 risk⁴⁹ by accounting for highly comorbid alcohol consumption, cannabis use, and SUDs, which when combined with reports suggesting smoking intensifies the severity of COVID-19 symptoms,^50,51 the risk for being admitted to an intensive care unit or requiring ventilation,⁵¹ and recent transcriptomics-based work showing that smoking may increase the expression of angiotensin converting enzyme 2 (ACE2), the putative receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (the virus that causes COVID-19),⁵² suggests smoking may be an important modifiable risk factor for COVID-19 risk.

Our genetics-based findings support and extend the observational literature identifying tobacco smoking as a risk factor for respiratory infection and diseases,^9,53,54 and add to the recent MR literature identifying potential causal links of smoking with reduced lung function⁵⁵, lung cancer,⁵⁶ and increased mortality due to respiratory disease.⁵⁷ Potential mechanisms by which smoking increases respiratory infection risk include structural changes to the respiratory tract and a dysregulated cellular and humoral immune response, including peribronchiolar inflammation, decreased levels of circulating immunoglobulins, and changes to pathogen adherence.⁵³ For example, smoking has been shown to stimulate the release of catecholamine and corticosteroids, which may, in turn, increase circulating CD8⁺ lymphocytes and suppress the host defense against infections.⁵³ Notably, many immunological effects related to smoking may resolve within six weeks of smoking cessation,⁵³ which suggests that smoking cessation programs may have an important impact on reducing respiratory infections.

Regarding cannabis use, to our knowledge this is the first MR study to investigate the role of cannabis use in respiratory infections, and while we failed to find evidence of any relationships, smoking cannabis, like tobacco smoking, may prompt the onset of coughing, which could consequently increase viral transmission, or may exacerbate possibly respiratory symptoms. As cannabis is the most used drug worldwide –an estimated 188 million recreational users worldwide⁵⁸ – this aspect of cannabis use may have important implications for the spread of COVID-19. In contrast, the single-variable MR CUD results demonstrated adverse effects on several respiratory outcomes, but not COPD, which supports the existing literature;^59–61 however, accounting for lifetime tobacco smoking attenuated highlighting the complex nature of these relationships. Further, habitual cannabis smoking may have several effects on respiratory and immune systems that may impact respiratory infection susceptibility: For example, structural abnormalities in alveolar macrophages and coincident dysregulated cytokine production and antimicrobial activity have been reported.⁶¹ While our study provides preliminary genetic evidence suggesting potential causal relationships between heavy cannabis use and respiratory infection, additional triangulating lines of evidence (i.e., immune monitoring studies), are required to further elucidate the CUD-respiratory infection relationship. However, the toxin and irritant profiles of cannabis and tobacco smoke are similar,¹¹ which suggests the direct route of administration via inhalation for these substances and may result in dysregulated pulmonary physiology which may, in turn, increase infection risk.

In contrast to our tobacco smoking findings, we failed to find genetic evidence of respiratory implications due to alcohol consumption not meeting threshold of AUD, or binge drinking, suggesting that previous observational literature may be due to confounding from other comorbid behaviors – such as smoking – that may be the true causal risk factors for respiratory infections. For example, observational and genetic evidence have shown a strong association between alcohol consumption and smoking: It has been estimated that 85% of smokers consume alcohol^62–64 and alcohol drinkers are 75% more likely than abstainers to smoke⁶⁵. Therefore, it is possible that the observational study-based alcohol-respiratory infection links may be due, instead, to tobacco smoking; however, future work will be needed to confirm this hypothesis. In addition, it is important to note that our results should not be interpreted as suggesting that alcohol does not impact overall lung health and structure, which has been previously reported.⁷ Further, while we failed to find evidence that weekly alcohol consumption impacted COVID-19 risk, the Centers for Disease Control recently showed that dining at on-site locations, such as restaurants and bars, is associated with increased COVID-19 risk,⁶⁶ and given that alcohol consumption may lower inhibition and increase impulsivity,⁶⁷ individuals consuming alcohol may take social distancing less seriously, and thereby unintentionally spread the SARS-CoV-2 virus.

This study has several strengths including the use of multiple alcohol consumption and cannabis use variables, which enabled us to evaluate various dimensions of substance use and abuse and identify possible causal relationships of substance use disorders and respiratory outcomes. In addition, our main single variable analyses included multiple MR methods, each relying on orthogonal assumptions, provides confidence in robustness of the results and strengthens causal inference.⁶⁸ Further, our multivariable two-sample MR design, the most appropriate design given the strong correlation between tobacco smoking, alcohol consumption and cannabis use, yielding estimates that account for these correlated behaviors for each exposure on COVID-19 risk and other respiratory outcomes.⁶⁹

This study also has limitations: For example, like existing self-reported substance use literature, these exposures may be either under- or over-reported.⁷⁰ Because many of the datasets included UK Biobank participants, who are more educated, with healthier lifestyles, and fewer health problems than the UK population,⁷¹ which may limit the applicability of our findings to other populations. Regarding our mainly null alcohol-respiratory infection results, it is possible that alcohol may have indirect impact on infection risk through a modified immune response,⁷² or other system dysregulation, that may modulate infection risk that we were not able to directly assess. Further, while we found some evidence that AUD may increase the risk for COVID-19; the largely null other current AUD findings does not support a broader AUD-respiratory disease relationship. However, like other recent psychiatric MR studies where the exposure instruments included a relaxed statistical threshold, our binge drinking and AUD instruments were comprised of independent SNPs associated with the respective drinking behavior (i.e., P-value < 5×10⁻⁶) for SNP inclusion due to the lack of conventionally GWS SNPs (P-value < 5×10⁻⁸),^29,30 which may impact the results. Because heavy alcohol consumption and AUD have been previously linked with acute respiratory distress syndrome¹⁰ – one of the most severe complications of COVID-19,⁷³ future studies re-evaluating the links between heavy alcohol consumption and AUD when better powered GWAS data becomes available.

In addition, the included samples were comprised of primarily white individuals of European ancestry, and research has shown strong racial, ethnic, and socioeconomic disparities in COVID-19 risk, and severity.^74–76 Therefore, we caution the generalization of these findings and urge future work to investigate these relationships using a genetics-based approach in other populations when the data becomes available. Another limitation is the overlap of the UKB participants between the alcohol consumption, lifetime smoking, and COVID-19 outcomes, which may bias resulting estimates;³⁹ however, any bias would likely be minimal.³⁹ It has been also shown that two-sample MR may be safely used in single samples provided the data is derived from large biobanks (i.e., the UKB, FinnGen, etc.,).⁷⁷

In conclusion, our data provide genetic evidence of adverse relationships between smoking and many respiratory-related disease outcomes ranging from the common cold to severe COVID-19, which suggests prevention programs aimed at smoking cessation and prevention may have public health and clinical benefits. We also observed a potential dose-dependent relationship where heavy substance use – as indicated by CUD – but not general cannabis use, was linked with several respiratory infections, suggesting heavy cannabis use may have a harmful impact on respiratory infections, which may have important respiratory-related consequences given the increasingly permissive cannabis-use laws.