Dataset Information

Cross-ancestry genetic investigation of schizophrenia, cannabis use disorder, and tobacco smoking.

ABSTRACT: Individuals with schizophrenia frequently experience co-occurring substance use, including tobacco smoking and heavy cannabis use, and substance use disorders. There is interest in understanding the extent to which these relationships are causal, and to what extent shared genetic factors play a role. We explored the relationships between schizophrenia (Scz), cannabis use disorder (CanUD), and ever-regular tobacco smoking (Smk) using the largest available genome-wide studies of these phenotypes in individuals of African and European ancestries. All three phenotypes were positively genetically correlated (r_gs = 0.17 - 0.62). Causal inference analyses suggested the presence of horizontal pleiotropy, but evidence for bidirectional causal relationships was also found between all three phenotypes even after correcting for horizontal pleiotropy. We identified 439 pleiotropic loci in the European ancestry data, 150 of which were novel (i.e., not genome-wide significant in the original studies). Of these pleiotropic loci, 202 had lead variants which showed convergent effects (i.e., same direction of effect) on Scz, CanUD, and Smk. Genetic variants convergent across all three phenotypes showed strong genetic correlations with risk-taking, executive function, and several mental health conditions. Our results suggest that both horizontal pleiotropy and causal mechanisms may play a role in the relationship between CanUD, Smk, and Scz, but longitudinal, prospective studies are needed to confirm a causal relationship.

SUBMITTER: Johnson EC

PROVIDER: S-EPMC10827265 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Cross-ancestry genetic investigation of schizophrenia, cannabis use disorder, and tobacco smoking.

Johnson Emma C EC Austin-Zimmerman Isabelle I Thorpe Hayley Ha HH Levey Daniel F DF Baranger David Aa DA Colbert Sarah Mc SM Demontis Ditte D Khokhar Jibran Y JY Davis Lea K LK Edenberg Howard J HJ Forti Marta Di MD Sanchez-Roige Sandra S Gelernter Joel J Agrawal Arpana A

medRxiv : the preprint server for health sciences 20240118

Individuals with schizophrenia frequently experience co-occurring substance use, including tobacco smoking and heavy cannabis use, and substance use disorders. There is interest in understanding the extent to which these relationships are causal, and to what extent shared genetic factors play a role. We explored the relationships between schizophrenia (Scz), cannabis use disorder (CanUD), and ever-regular tobacco smoking (Smk) using the largest available genome-wide studies of these phenotypes i ...[more]

PMID: 38293235

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Project description:ImportanceDespite public health concerns that cannabis legalization may increase the number of cases of schizophrenia caused by cannabis, there is limited evidence on this topic.ObjectiveTo examine changes in the population-attributable risk fraction (PARF) for cannabis use disorder (CUD) associated with schizophrenia after liberalization of medical cannabis and legalization of nonmedical cannabis in Canada.Design, setting, and participantsThis population-based cohort study was conducted in Ontario, Canada, from January 1, 2006, to December 31, 2022, among 13 588 681 people aged 14 to 65 years without a history of schizophrenia.ExposuresDiagnosis of CUD in the emergency department or hospital setting (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Canada [ICD-10-CA] codes F12x and T40.7).Main outcome and measuresChanges in the PARF for CUD associated with schizophrenia (ICD-10-CA codes F20x and F25x and Diagnostic and Statistical Manual of Mental Disorders [Fourth Edition] [DSM-IV] code 295x) over 3 policy periods: prelegalization (January 2006 to November 2015), liberalization of medical and nonmedical cannabis (December 2015 to September 2018), and legalization of nonmedical cannabis (October 2018 to December 2022). A secondary outcome was diagnosis of psychosis not otherwise specified (NOS) (ICD-10-CA code F29x and DSM-IV code 298x). Segmented linear regression was used to examine changes after the liberalization of medical cannabis in 2015 and the legalization of nonmedical cannabis in 2018.ResultsThe study included 13 588 681 individuals (mean [SD] age, 39.3 [16.1] years; 6 804 906 males [50.1%]), of whom 118 650 (0.9%) had CUD. A total of 91 106 individuals (0.7%) developed schizophrenia (80 523 of 13 470 031 [0.6%] in the general population without CUD vs 10 583 of 118 650 [8.9%] with CUD). The PARF for CUD associated with schizophrenia almost tripled from 3.7% (95% CI, 2.7%-4.7%) during the prelegalization period to 10.3% (95% CI, 8.9%-11.7%) during the legalization period. The PARF in the postlegalization period ranged from 18.9% (95% CI, 16.8%-21.0%) among males aged 19 to 24 years to 1.8% (95% CI, 1.1%-2.6%) among females aged 45 to 65 years. The annual incidence of schizophrenia was stable over time, while the incidence of psychosis NOS increased from 30.0 to 55.1 per 100 000 individuals (83.7%) in the postlegalization period relative to the prelegalization period. The PARF for CUD associated with schizophrenia increased steadily over the study with no accelerations after cannabis policy changes, while increases in the PARF for CUD associated with psychosis NOS accelerated after medical cannabis liberalization.Conclusions and relevanceIn this cohort study of individuals aged 14 to 65 years in Ontario, Canada, the proportion of incident cases of schizophrenia associated with CUD almost tripled during a period of substantial liberalization of cannabis policy. Ongoing research is indicated to understand the long-term associations of cannabis policy with the prevalence of psychotic disorders.

Project description:BackgroundVulnerability to COVID-19 hospitalization has been linked to behavioral risk factors, including combustible psychoactive substance use (e.g., tobacco smoking). Paralleling the COVID-19 pandemic crisis have been increasingly permissive laws for recreational cannabis use. Cannabis use disorder (CUD) is a psychiatric disorder that is heritable and genetically correlated with respiratory disease, independent of tobacco smoking. We examined the genetic relationship between CUD and COVID-19 hospitalization.MethodsWe estimated the genetic correlation between CUD (case: n = 14,080; control: n = 343,726) and COVID-19 hospitalization (case: n = 9373; control: n = 1,197,256) using summary statistics from genome-wide association studies. Using independent genome-wide association studies conducted before the pandemic, we controlled for several covariates (i.e., tobacco use phenotypes, problematic alcohol use, body mass index, fasting glucose, forced expiratory volume, education attainment, risk taking, attention-deficit/hyperactivity disorder, Townsend deprivation index, chronic obstructive pulmonary disease, hypertension, and type 2 diabetes) using genomic structural equation modeling. Genetic causality between CUD and COVID-19 hospitalization was estimated using latent causal variable models.ResultsGenetic vulnerability to COVID-19 was correlated with genetic liability to CUD (r G = 0.423 [SE = 0.0965], p = 1.33 × 10-6); this association remained when accounting for genetic liability to related risk factors and covariates (b = 0.381-0.539, p = .012-.049). Latent causal variable analysis revealed causal effect estimates that were not statistically significant.ConclusionsProblematic cannabis use and vulnerability to serious COVID-19 complications share genetic underpinnings that are unique from common correlates. While CUD may plausibly contribute to severe COVID-19 presentations, causal inference models yielded no evidence of putative causation. Curbing excessive cannabis use may mitigate the impact of COVID-19.

Dataset Information

Cross-ancestry genetic investigation of schizophrenia, cannabis use disorder, and tobacco smoking.

Publications

Cross-ancestry genetic investigation of schizophrenia, cannabis use disorder, and tobacco smoking.

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