Emma C Johnson1, Alexander S Hatoum1, Joseph D Deak2,3, Renato Polimanti2,3, Robin M Murray4, Howard J Edenberg5,6, Joel Gelernter2,3,7, Marta Di Forti8, Arpana Agrawal1. 1. Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA. 2. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. 3. Department of Psychiatry, Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA. 4. Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. 5. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. 6. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA. 7. Departments of Genetics and Neuroscience, Yale University School of Medicine, New Haven, CT, USA. 8. Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Abstract
BACKGROUND AND AIMS: While epidemiological studies support a role for heavy, high-potency cannabis use on first-episode psychosis, genetic models of causation suggest reverse causal effects of schizophrenia on cannabis use liability. We estimated the genetic relationship between cannabis use disorder (CUD) and schizophrenia (SCZ) and tested whether liability for CUD is causally associated with increased liability to SCZ while adjusting for tobacco smoking. DESIGN: This study used summary statistics from published genome-wide association studies (GWAS). We used genomic structural equation modeling, latent causal variable analysis, and multivariable Mendelian randomization to examine genetic relationships between CUD, cannabis ever-use, ever-smoked tobacco regularly, nicotine dependence and SCZ, and to test for a causal relationship between liability to CUD and liability to SCZ. SETTING: Genome-wide association studies were published previously as part of international consortia. PARTICIPANTS: Sample sizes of the GWAS summary statistics used in this study ranged from 161 405 to 357 806 individuals of European ancestry. MEASUREMENTS: Genome-wide summary statistics for CUD and SCZ were the primary measurements, while summary statistics for cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence were included as additional variables in the genomic structural equation models and the multivariable Mendelian randomization analyses. FINDINGS: Genetic liability to CUD was significantly associated with SCZ [β = 0.29, 95% confidence interval (CI) = 0.11, 0.46, P = 0.001], even when accounting for cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence as simultaneous predictors. We found mixed evidence of a causal relationship, with the latent causal variable analysis finding no evidence of causality (genetic causality proportion = -0.08, 95% CI = -0.40, 0.23, P = 0.87) but the multivariable Mendelian randomization analyses suggesting a significant, risk-increasing effect of CUD on liability to SCZ (β = 0.10, 95% CI = 0.02, 0.18, P = 0.02), accounting for the additional risk factors (cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence). CONCLUSIONS: Genetic liability for cannabis use disorder appears to be robustly associated with schizophrenia, above and beyond tobacco smoking and cannabis ever-use, with mixed evidence to support a causal relationship between cannabis use disorder and schizophrenia.
BACKGROUND AND AIMS: While epidemiological studies support a role for heavy, high-potency cannabis use on first-episode psychosis, genetic models of causation suggest reverse causal effects of schizophrenia on cannabis use liability. We estimated the genetic relationship between cannabis use disorder (CUD) and schizophrenia (SCZ) and tested whether liability for CUD is causally associated with increased liability to SCZ while adjusting for tobacco smoking. DESIGN: This study used summary statistics from published genome-wide association studies (GWAS). We used genomic structural equation modeling, latent causal variable analysis, and multivariable Mendelian randomization to examine genetic relationships between CUD, cannabis ever-use, ever-smoked tobacco regularly, nicotine dependence and SCZ, and to test for a causal relationship between liability to CUD and liability to SCZ. SETTING: Genome-wide association studies were published previously as part of international consortia. PARTICIPANTS: Sample sizes of the GWAS summary statistics used in this study ranged from 161 405 to 357 806 individuals of European ancestry. MEASUREMENTS: Genome-wide summary statistics for CUD and SCZ were the primary measurements, while summary statistics for cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence were included as additional variables in the genomic structural equation models and the multivariable Mendelian randomization analyses. FINDINGS: Genetic liability to CUD was significantly associated with SCZ [β = 0.29, 95% confidence interval (CI) = 0.11, 0.46, P = 0.001], even when accounting for cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence as simultaneous predictors. We found mixed evidence of a causal relationship, with the latent causal variable analysis finding no evidence of causality (genetic causality proportion = -0.08, 95% CI = -0.40, 0.23, P = 0.87) but the multivariable Mendelian randomization analyses suggesting a significant, risk-increasing effect of CUD on liability to SCZ (β = 0.10, 95% CI = 0.02, 0.18, P = 0.02), accounting for the additional risk factors (cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence). CONCLUSIONS: Genetic liability for cannabis use disorder appears to be robustly associated with schizophrenia, above and beyond tobacco smoking and cannabis ever-use, with mixed evidence to support a causal relationship between cannabis use disorder and schizophrenia.
Authors: Joëlle A Pasman; Karin J H Verweij; Zachary Gerring; Sven Stringer; Sandra Sanchez-Roige; Jorien L Treur; Abdel Abdellaoui; Michel G Nivard; Bart M L Baselmans; Jue-Sheng Ong; Hill F Ip; Matthijs D van der Zee; Meike Bartels; Felix R Day; Pierre Fontanillas; Sarah L Elson; Harriet de Wit; Lea K Davis; James MacKillop; Jaime L Derringer; Susan J T Branje; Catharina A Hartman; Andrew C Heath; Pol A C van Lier; Pamela A F Madden; Reedik Mägi; Wim Meeus; Grant W Montgomery; A J Oldehinkel; Zdenka Pausova; Josep A Ramos-Quiroga; Tomas Paus; Marta Ribases; Jaakko Kaprio; Marco P M Boks; Jordana T Bell; Tim D Spector; Joel Gelernter; Dorret I Boomsma; Nicholas G Martin; Stuart MacGregor; John R B Perry; Abraham A Palmer; Danielle Posthuma; Marcus R Munafò; Nathan A Gillespie; Eske M Derks; Jacqueline M Vink Journal: Nat Neurosci Date: 2018-08-27 Impact factor: 24.884
Authors: Arianna Marconi; Marta Di Forti; Cathryn M Lewis; Robin M Murray; Evangelos Vassos Journal: Schizophr Bull Date: 2016-02-15 Impact factor: 9.306
Authors: Chandni Hindocha; Tom P Freeman; Jason A Ferris; Michael T Lynskey; Adam R Winstock Journal: Front Psychiatry Date: 2016-07-05 Impact factor: 4.157
Authors: Bryan C Quach; Michael J Bray; Nathan C Gaddis; Mengzhen Liu; Teemu Palviainen; Camelia C Minica; Stephanie Zellers; Richard Sherva; Fazil Aliev; Michael Nothnagel; Kendra A Young; Jesse A Marks; Hannah Young; Megan U Carnes; Yuelong Guo; Alex Waldrop; Nancy Y A Sey; Maria T Landi; Daniel W McNeil; Dmitriy Drichel; Lindsay A Farrer; Christina A Markunas; Jacqueline M Vink; Jouke-Jan Hottenga; William G Iacono; Henry R Kranzler; Nancy L Saccone; Michael C Neale; Pamela Madden; Marcella Rietschel; Mary L Marazita; Matthew McGue; Hyejung Won; Georg Winterer; Richard Grucza; Danielle M Dick; Joel Gelernter; Neil E Caporaso; Timothy B Baker; Dorret I Boomsma; Jaakko Kaprio; John E Hokanson; Scott Vrieze; Laura J Bierut; Eric O Johnson; Dana B Hancock Journal: Nat Commun Date: 2020-11-03 Impact factor: 17.694
Authors: Catherine A Dennen; Kenneth Blum; Abdalla Bowirrat; Jag Khalsa; Panayotis K Thanos; David Baron; Rajendra D Badgaiyan; Ashim Gupta; Eric R Braverman; Mark S Gold Journal: Epigenomes Date: 2022-08-26