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Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample Mendelian randomization study.

ABSTRACT: BACKGROUND:Observational associations between cannabis and schizophrenia are well documented, but ascertaining causation is more challenging. We used Mendelian randomization (MR), utilizing publicly available data as a method for ascertaining causation from observational data. METHOD:We performed bi-directional two-sample MR using summary-level genome-wide data from the International Cannabis Consortium (ICC) and the Psychiatric Genomics Consortium (PGC2). Single nucleotide polymorphisms (SNPs) associated with cannabis initiation (p < 10-5) and schizophrenia (p < 5 × 10-8) were combined using an inverse-variance-weighted fixed-effects approach. We also used height and education genome-wide association study data, representing negative and positive control analyses. RESULTS:There was some evidence consistent with a causal effect of cannabis initiation on risk of schizophrenia [odds ratio (OR) 1.04 per doubling odds of cannabis initiation, 95% confidence interval (CI) 1.01-1.07, p = 0.019]. There was strong evidence consistent with a causal effect of schizophrenia risk on likelihood of cannabis initiation (OR 1.10 per doubling of the odds of schizophrenia, 95% CI 1.05-1.14, p = 2.64 × 10-5). Findings were as predicted for the negative control (height: OR 1.00, 95% CI 0.99-1.01, p = 0.90) but weaker than predicted for the positive control (years in education: OR 0.99, 95% CI 0.97-1.00, p = 0.066) analyses. CONCLUSIONS:Our results provide some that cannabis initiation increases the risk of schizophrenia, although the size of the causal estimate is small. We find stronger evidence that schizophrenia risk predicts cannabis initiation, possibly as genetic instruments for schizophrenia are stronger than for cannabis initiation.

SUBMITTER: Gage SH

PROVIDER: S-EPMC5341491 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample Mendelian randomization study.

Gage S H SH Jones H J HJ Burgess S S Bowden J J Davey Smith G G Zammit S S Munafò M R MR

Psychological medicine 20161208 5

<h4>Background</h4>Observational associations between cannabis and schizophrenia are well documented, but ascertaining causation is more challenging. We used Mendelian randomization (MR), utilizing publicly available data as a method for ascertaining causation from observational data.<h4>Method</h4>We performed bi-directional two-sample MR using summary-level genome-wide data from the International Cannabis Consortium (ICC) and the Psychiatric Genomics Consortium (PGC2). Single nucleotide polymo ...[more]

PMID: 27928975

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Project description:BackgroundThe use of cannabis has increased globally due to more regions decriminalizing marijuana use for therapeutic and recreational aims. Several observational studies have revealed that cannabis use is associated with an increased risk of adverse cardiovascular pathologies and diseases. Nevertheless, the causal associations between cannabis use and cardiovascular diseases remain unclear. Hence, we performed single-variable and multivariable Mendelian randomization (MR) to evaluate the association between cannabis use disorder and various cardiovascular diseases.Materials and methodsSummary statistics were collected from the largest-to-date genome-wide association studies (GWAS) of cannabis use disorder. The 12 SNPs for cannabis use disorder were used as instrumental variables in this study. MR estimates were pooled using a random-effects inverse-variance weighted (IVW) method. Simple median and weighted median methods were conducted as sensitivity analyses.ResultsThe genetic liability to cannabis use disorder was associated with an augmented risk of coronary artery disease, myocardial infarction, atrial fibrillation, heart failure, deep venous thrombosis, pulmonary embolism, and stroke. Except for stroke, the results were inconsistent in the sensitivity analyses. The overall patterns for the associations of cannabis use disorder with atrial fibrillation, heart failure, pulmonary embolism and stroke remained in multivariable MR analyses adjusting for potential mediators, including smoking, alcohol, body mass index, blood lipid, type 2 diabetes, hypertension, and depression. However, the association with coronary artery disease, myocardial infarction, and deep venous thrombosis did not persist in multivariable MR analyses. Mediation analysis demonstrated that smoking, body mass index, low-density lipoprotein, hypertension, and depression have more significant mediation effects, which suggests that these factors partly mediate the link from cannabis use disorder to coronary artery disease, myocardial infarction, and deep venous thrombosis.ConclusionThe genetic liability to cannabis use disorder was associated with a higher risk of atrial fibrillation, heart failure, pulmonary embolism, and stroke. The evidence for the association between cannabis use disorder, coronary artery disease, myocardial infarction, and deep venous thrombosis was weak. Hence, future use of cannabis for therapeutic and recreational aims should consider its potential impact on cardiovascular diseases.

Project description:Rationale & objectiveThe association between cannabis use and chronic kidney disease (CKD) is controversial. We aimed to assess association of CKD with cannabis use in a large cohort study and then assess causality using Mendelian randomization with a genome-wide association study (GWAS).Study designRetrospective cohort study and genome-wide association study.Setting & participantsThe retrospective study was conducted on the All of Us cohort (N=223,354). Genetic instruments for cannabis use disorder were identified from 3 GWAS: the Psychiatric Genomics Consortium Substance Use Disorders, iPSYCH, and deCODE (N=384,032). Association between genetic instruments and CKD was investigated in the CKDGen GWAS (N > 1.2 million).ExposureCannabis consumption.OutcomesCKD outcomes included: cystatin-C and creatinine-based kidney function, proteinuria, and blood urea nitrogen.Analytical approachWe conducted association analyses to test for frequency of cannabis use and CKD. To evaluate causality, we performed a 2-sample Mendelian randomization.ResultsIn the retrospective study, compared to former users, less than monthly (OR, 1.01; 95% CI, 0.87-1.18; P = 0.87) and monthly cannabis users (OR, 1.15; 95% CI, 0.86-1.52; P = 0.33) did not have higher CKD odds. Conversely, weekly (OR, 1.28; 95% CI, 1.01-1.60; P = 0.04) and daily use (OR, 1.25; 95% CI, 1.04-1.50; P = 0.02) was significantly associated with CKD, adjusted for multiple confounders. In Mendelian randomization, genetic liability to cannabis use disorder was not associated with increased odds for CKD (OR, 1.00; 95% CI, 0.99-1.01; P = 0.96). These results were robust across different Mendelian randomization techniques and multiple kidney traits.LimitationsLikely underreporting of cannabis use. In Mendelian randomization, genetic instruments were identified in the GWAS that included individuals primarily of European ancestry.ConclusionsDespite the epidemiological association between cannabis use and CKD, there was no evidence of a causal effect, indicating confounding in observational studies.

Dataset Information

Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample Mendelian randomization study.

Publications

Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample Mendelian randomization study.

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