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

Addiction ◽  
2021 ◽  
Author(s):  
Zoe E. Reed ◽  
Robyn E. Wootton ◽  
Marcus R. Munafò
Keyword(s):  
Substance Use ◽  
Alcohol Consumption ◽  
Mendelian Randomization ◽  
Smoking Initiation ◽  
Causal Effects ◽  
Gateway Hypothesis

scholarly journals Evidence for Causal Effects of Smoking Initiation and Alcohol Consumption on Substance Use Outcomes

2021 ◽  
Author(s):  
Zoe E. Reed ◽  
Robyn E. Wootton ◽  
Marcus R. Munafò
Keyword(s):  
Substance Use ◽  
Risk Factor ◽  
Alcohol Consumption ◽  
Opioid Dependence ◽  
Smoking Initiation ◽  
Cannabis Use ◽  
Causal Effects ◽  
P Value ◽  
Gateway Hypothesis ◽  
Shared Risk

AbstractBackground and AimsThe ‘gateway’ hypothesis proposes that initial use of drugs such as tobacco and alcohol can lead to subsequent more problematic drug use. However, it is unclear whether true casual pathways exist, or whether there is instead a shared underlying risk factor. We used bidirectional Mendelian Randomisation (MR) to test these two competing hypotheses.MethodsWe conducted two-sample MR analyses, using genome-wide association data for smoking initiation, alcoholic drinks per week, cannabis use and dependence, cocaine and opioid dependence. We used several MR methods that rely on different assumptions: inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode and weighted mode. Consistent results across these methods would support stronger inference.ResultsWe found evidence of causal effects from smoking initiation to increased drinks per week (IVW: β=0.06; 95% CI 0.03 to 0.09; p-value=9.44×10-06), cannabis use (IVW: OR=1.34; 95% CI 1.24 to 1.44; p-value=1.95×10-14), and cannabis dependence (IVW: OR=1.68; 95% CI 1.12 to 2.51; p-value=0.01). We also found evidence of an effect of cannabis use on increased likelihood of smoking initiation (IVW: OR=1.39; 95% CI=1.08 to 1.80; p-value=0.01). We did not find evidence of an effect of drinks per week on substance use outcomes, except for weak evidence of an effect on cannabis use. We also found evidence of an effect of opioid dependence on increased drinks per week (IVW: β=0.002; 95% CI=0.0005 to 0.003; p-value=8.61×10-03).ConclusionsOverall, we found evidence suggesting a causal pathway from smoking initiation to alcohol consumption, and both cannabis use and dependence, which may support the gateway hypothesis. However, we also found causal effects of cannabis use on smoking initiation, and opioid dependence on alcohol consumption, which suggests the existence of a shared risk factor. Further research should explore whether this is the case, and in particular the nature of any shared risk factors.

scholarly journals Investigating causal pathways between liability to ADHD and substance use, and liability to substance use and ADHD risk, using Mendelian randomization

2019 ◽  
Author(s):  
Jorien L Treur ◽  
Ditte Demontis ◽  
George Davey Smith ◽  
Hannah Sallis ◽  
Tom G Richardson ◽  
...  
Keyword(s):  
Substance Use ◽  
Alcohol Use ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Smoking Initiation ◽  
Cannabis Use ◽  
Causal Effects ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Causal Pathways

ABSTRACTBackgroundAttention-deficit hyperactivity disorder (ADHD) has consistently been associated with substance (ab)use, but the nature of this association is not fully understood. In view of preventive efforts, a vital question is whether there are causal effects, from ADHD to substance use and/or from substance use to ADHD.MethodsWe applied bidirectional Mendelian randomization using summary-level data from the largest available genome-wide association studies (GWASs) on ADHD, smoking (initiation, cigarettes/day, cessation, and a compound measure of lifetime smoking), alcohol use (drinks/week and alcohol use disorder), cannabis use (initiation and cannabis use disorder (CUD)) and coffee consumption (cups/day). Genetic variants robustly associated with the ‘exposure’ were selected as instruments and then identified in the ‘outcome’ GWAS. Effect estimates from individual genetic variants were combined with inverse-variance weighted regression and five sensitivity analyses were applied (weighted median, weighted mode, MR-Egger, generalized summary-data-based MR, and Steiger filtering).ResultsWe found strong evidence that liability to ADHD increases likelihood of smoking initiation and also cigarettes per day among smokers, decreases likelihood of smoking cessation, and increases likelihood of cannabis initiation and CUD. In the other direction, there was evidence that liability to smoking initiation and CUD increase ADHD risk. There was no clear evidence of causal effects between liability to ADHD and alcohol or caffeine consumption.ConclusionsWe find evidence for causal effects of liability to ADHD on smoking and cannabis use, and of liability to smoking and cannabis use on ADHD risk, indicating bidirectional pathways. Further work is needed to explore causal mechanisms.

scholarly journals Gallstone disease, diabetes, calcium, triglycerides, smoking and alcohol consumption and pancreatitis risk: Mendelian randomization study

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Shuai Yuan ◽  
Edward L. Giovannucci ◽  
Susanna C. Larsson
Keyword(s):  
Type 2 Diabetes ◽  
Chronic Pancreatitis ◽  
Alcohol Consumption ◽  
Mendelian Randomization ◽  
Gallstone Disease ◽  
Smoking Initiation ◽  
Disease Type ◽  
Uk Biobank ◽  
Increased Risk

AbstractWe conducted a Mendelian randomization study to determine the potential causal associations of gallstone disease, diabetes, serum calcium, triglyceride levels, smoking and alcohol consumption with acute and chronic pancreatitis. Genetic variants associated with the exposures at p < 5 × 10−8 were selected from corresponding genome-wide association studies. Summary-level data for pancreatitis were obtained from the FinnGen consortium and UK Biobank. Univariable and multivariable Mendelian randomization analyses were performed and results from FinnGen and UK Biobank were combined using the fixed-effects meta-analysis method. Genetic predisposition to gallstone disease, type 2 diabetes and smoking initiation was associated with an increased risk of acute pancreatitis. The combined odds ratios (ORs) were 1.74 (95% confidence interval (CI), 1.57, 1.93) for gallstone disease, 1.14 (95% CI, 1.06, 1.21) for type 2 diabetes and 1.56 (95% CI, 1.32, 1.83) for smoking initiation. The association for type 2 diabetes attenuated after adjustment for gallstone disease. Genetic predisposition to gallstone disease and smoking initiation as well as higher genetically predicted serum calcium and triglyceride levels were associated with an increased risk of chronic pancreatitis. The combined ORs of chronic pancreatitis were 1.27 (95% CI, 1.08, 1.50) for gallstone disease, 1.86 (95% CI, 1.43, 2.43) for smoking initiation, 2.20 (95% CI, 1.30, 3.72) for calcium and 1.47 (95% CI, 1.23, 1.76) for triglycerides. This study provides evidence in support that gallstone disease, type 2 diabetes, smoking and elevated calcium and triglyceride levels are causally associated with the risk of acute or chronic pancreatitis.

scholarly journals Is there a causal relationship between executive function and liability to mental health and substance use? A Mendelian randomisation approach

2022 ◽  
Author(s):  
Sabrina M.I Burton ◽  
Hannah M Sallis ◽  
Alexander S Hatoum ◽  
Marcus R Munafo ◽  
Zoe E Reed
Keyword(s):  
Mental Health ◽  
Substance Use ◽  
Executive Function ◽  
Alcohol Consumption ◽  
Causal Relationship ◽  
Causal Effect ◽  
Smoking Initiation ◽  
Mendelian Randomisation ◽  
P Value ◽  
Causal Relationships

Background: Executive function consists of several cognitive control processes that are able to regulate lower level processes. Poorer performance in tasks designed to test executive function is associated with a range of psychopathologies such as schizophrenia, major depressive disorder (MDD) and anxiety, as well as with smoking and alcohol consumption. Despite these well-documented associations, whether they reflect causal relationships, and if so in what direction, remains unclear. We aimed to establish whether there is a causal relationship between a latent factor for performance on multiple executive function tasks - which we refer to as common executive function (cEF) - and liability to schizophrenia, MDD, anxiety, smoking initiation, alcohol consumption, alcohol dependence and cannabis use disorder (CUD), and the directionality of any relationship observed. Methods: We used a two-sample bidirectional Mendelian randomisation (MR) approach using genome-wide association study (GWAS) summary data from large cohorts (N=17,310 to 848,460) to examine whether causal relationships exist, and if so in which direction. Results: We found evidence of a causal effect of increased cEF on reduced schizophrenia liability (IVW: OR=0.10; 95% CI 0.05 to 0.19; p-value=3.43x10-12), reduced MDD liability (IVW: OR=0.52; 95% CI 0.38 to 0.72; p-value=5.23x10-05), decreased drinks per week (IVW: β=-0.06; 95% CI -0.10 to -0.02; p-value=0.003), and reduced CUD liability (IVW: OR=0.27; 95% CI 0.12 to 0.61; p-value=1.58x10-03). We also found evidence of a causal effect of increased schizophrenia liability on decreased cEF (IVW: β=-0.04; 95% CI -0.04 to -0.03; p-value=3.25x10-27), as well as smoking initiation on decreased cEF (IVW: β=-0.06; 95%CI -0.09 to -0.03; p-value=6.11x10-05). Conclusion: Our results indicate a potential bidirectional causal relationship between a latent factor measure of executive function (cEF) and schizophrenia liability, a possible causal effect of increased cEF on reduced MDD liability, CUD liability, and alcohol consumption, and a possible causal effect of smoking initiation on decreased cEF. These results suggest that executive function should be considered as a potential risk factor for some mental health and substance use outcomes, and may also be impacted by mental health (particularly schizophrenia). Further studies are required to improve our understanding of the underlying mechanisms of these effects, but our results suggest that executive function may be a promising intervention target. These results may therefore inform the prioritisation of experimental medicine studies (e.g., of executive function interventions), for both mental health and substance use outcomes, to improve the likelihood of successful translation.

scholarly journals Causal relationships between substance use and insomnia

2020 ◽  
Author(s):  
Joëlle A. Pasman ◽  
Dirk J.A. Smit ◽  
Lilian Kingma ◽  
Jacqueline M. Vink ◽  
Jorien L. Treur ◽  
...  
Keyword(s):  
Substance Use ◽  
Alcohol Use ◽  
Alcohol Dependence ◽  
Strong Evidence ◽  
Smoking Initiation ◽  
Causal Effects ◽  
Sensitivity Analyses ◽  
Poor Sleep ◽  
A Genome ◽  
Bidirectional Effects

AbstractBackgroundPoor sleep quality and insomnia have been associated with the use of tobacco, alcohol, and cannabis, but it is unclear if there is a causal link. In this Mendelian Randomization (MR) study we examine if insomnia causes substance use and/or if substance use causes insomnia.MethodsMR uses summary effect estimates from a genome-wide association study (GWAS) to create a genetic instrumental variable for a proposed ‘exposure’ variable and then identifies that same genetic instrument in an ‘outcome’ GWAS. With data of GWAS of insomnia, smoking (initiation, heaviness, cessation), alcohol use (drinks per week, dependence), and cannabis initiation, bi-directional causal effects were tested. Multiple sensitivity analyses were applied to assess the robustness of the findings.ResultsThere was strong evidence for positive causal effects of insomnia on all substance use phenotypes (smoking traits, alcohol dependence, cannabis initiation), except alcohol per week. The effects on alcohol dependence and cannabis initiation were attenuated after filtering out pleiotropic SNPs. In the other direction, there was strong evidence that smoking initiation increased chances of insomnia (smoking heaviness and cessation could not be tested as exposures). We found no evidence that alcohol use per week, alcohol dependence, or cannabis initiation causally affect insomnia.ConclusionsThere were unidirectional effects of insomnia on alcohol dependence and cannabis initiation, and bidirectional effects between insomnia and smoking measures. Bidirectional effects between smoking and insomnia might give rise to a vicious circle. Future research should investigate if interventions aimed at insomnia are beneficial for substance use treatment.

scholarly journals Cigarette Smoking, Coffee Consumption, Alcohol Intake, and Risk of Crohn’s Disease and Ulcerative Colitis: A Mendelian Randomization Study

2020 ◽  
Author(s):  
Andrea N Georgiou ◽  
Georgios Ntritsos ◽  
Nikos Papadimitriou ◽  
Niki Dimou ◽  
Evangelos Evangelou
Keyword(s):  
Ulcerative Colitis ◽  
Sensitivity Analysis ◽  
Crohn’S Disease ◽  
Alcohol Consumption ◽  
Crohn's Disease ◽  
Cigarette Smoking ◽  
Mendelian Randomization ◽  
Coffee Consumption ◽  
Smoking Initiation ◽  
Causal Association

Abstract Background Crohn’s disease (CD) and ulcerative colitis (UC) are widely associated with smoking in epidemiological studies, whereas there are conflicting results for the association between CD and UC for both coffee and alcohol consumption. Herein, we aimed to investigate whether cigarette smoking and alcohol and coffee consumption are causally associated with either CD or UC. Methods We utilized 540 genome-wide significant single-nucleotide polymorphisms for 3 potentially addictive substances—nicotine, alcohol, and caffeine—to assess the association of smoking, coffee, and alcohol consumption with CD and UC (12,194 CD cases, 12,366 UC cases, and 25,042 controls of European ancestry), using Mendelian randomization analysis. Mendelian randomization estimates were used to evaluate the effect of the exposure factors on CD and UC risk. Sensitivity analysis was employed to test for any directional pleiotropy. Results We found evidence for a positive causal association between the age of smoking initiation and UC risk and between alcohol consumption and CD risk, which disappeared after sensitivity analysis for both associations (P &gt; 0.05). No evidence for a causal association between cigarettes per day, smoking initiation, smoking cessation, and coffee consumption variables and UC or CD was found. Conclusions We found no clear evidence that either genetically predicted smoking, coffee consumption, or alcohol consumption are causally associated with the risk for CD or UC, although our findings indicate a potential positive association between the age of smoking and UC and between alcohol consumption and CD.

scholarly journals Mendelian randomization analysis provides causality of smoking on the expression of ACE2, a putative SARS-CoV-2 receptor

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Hui Liu ◽  
Junyi Xin ◽  
Sheng Cai ◽  
Xia Jiang
Keyword(s):  
Alcohol Consumption ◽  
Research Council ◽  
Mendelian Randomization ◽  
Smoking Initiation ◽  
Smoking Intensity ◽  
Swedish Research Council ◽  
Inverse Variance ◽  
Nominal Significance ◽  
Weighted Median

Background: To understand a causal role of modifiable lifestyle factors in ACE2 expression (a putative SARS-CoV-2 receptor) across 44 human tissues/organs, and in COVID-19 susceptibility and severity, we conducted a phenome-wide two-sample Mendelian randomization (MR) study. Methods: More than 500 genetic variants were used as instrumental variables to predict smoking and alcohol consumption. Inverse-variance weighted approach was adopted as the primary method to estimate a causal association, while MR-Egger regression, weighted median and MR-PRESSO were performed to identify potential horizontal pleiotropy. Results: We found that genetically predicted smoking intensity significantly increased ACE2 expression in thyroid (β=1.468, p=1.8 10-8); and increased ACE2 expression in adipose, brain, colon and liver with nominal significance. Additionally, genetically predicted smoking initiation significantly increased the risk of COVID-19 onset (odds ratio=1.14, p=8.7 10-5). No statistically significant result was observed for alcohol consumption. Conclusions: Our work demonstrates an important role of smoking, measured by both status and intensity, in the susceptibility to COVID-19. Funding: Dr. Jiang is supported by research grants from the Swedish Research Council (VR-2018-02247) and Swedish Research Council for Health, Working Life and Welfare (FORTE-2020-00884).

Exploring a causal model in observational cohort data: The role of parents and peers in shaping substance use trajectories

2020 ◽  
Author(s):  
Christopher Greenwood ◽  
George Joseph Youssef ◽  
Primrose Letcher ◽  
Elizabeth Spry ◽  
Lauryn Hagg ◽  
...  
Keyword(s):  
Substance Use ◽  
Cannabis Use ◽  
Causal Effects ◽  
Deviant Peers ◽  
Adolescent Relationships ◽  
Cohort Data ◽  
Observational Cohort ◽  
Peer Affiliations ◽  
Role Of Parents ◽  
Adolescent Relationship

Aims: To explore the process of applying counterfactual thinking in examining causal predictors of substance use trajectories in observational cohort data. Specifically, we examine the extent to which quality of the parent-adolescent relationship and affiliations with deviant peers are causally related to trajectories of alcohol, tobacco, and cannabis use across adolescence and into young adulthood. Methods: Data were drawn from the Australian Temperament Project, a population-based cohort study that has followed a sample of young Australians from infancy to adulthood since 1983. Parent-adolescent relationship quality and deviant peer affiliations were assessed at age 13-14 years. Latent curve models were fitted for past month alcohol, tobacco, and cannabis use (n = 1,590) from age 15-16 to 27-28 years (5 waves). Confounding factors were selected in line with the counterfactual framework. Results: Following confounder adjustment, higher quality parent-adolescent relationships were associated with lower baseline cannabis use, but not alcohol or tobacco use trajectories. In contrast, affiliations with deviant peers were associated with higher baseline binge drinking, tobacco, and cannabis use, and an earlier peak in the cannabis use trajectory. Conclusions: Confounding adjustments weakened several estimated associations and the interpretation of such associations as causal is not without limitations. Nevertheless, findings suggested causal effects of both parent-adolescent relationships and deviant peer affiliations on the trajectory of substance use. Causal effects were however more pervasive (i.e., more substance types) and protracted for deviant peer affiliations. The current study encourages the exploration of causal relationships in observational cohort data, when relevant limitations are transparently acknowledged.

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