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No evidence of associations between genetic liability for schizophrenia and development of cannabis use disorder

  • Carsten Hjorthøj (a1) (a2) (a3), Md Jamal Uddin (a1) (a2), Theresa Wimberley (a2) (a4) (a5), Søren Dalsgaard (a2) (a4), David M. Hougaard (a2) (a6), Anders Børglum (a2) (a7), Thomas Werge (a2) (a8) and Merete Nordentoft (a1) (a2)...

Abstract

Background

Cannabis use and cannabis use disorder (CUD) is increased in patients with schizophrenia. It is important to establish if this is explained by non-causal factors, such as shared genetic vulnerability. We aimed to investigate whether the polygenic risk scores (PRS) for schizophrenia and other psychiatric disorders would predict CUD in controls, patients with schizophrenia, and patients with other psychiatric disorders.

Methods

We linked nationwide Danish registers and genetic information obtained from dried neonatal bloodspots in an observational analysis. We included people with schizophrenia, other psychiatric disorders, and controls. The exposures of interest were the PRS for schizophrenia, attention-deficit hyperactivity disorder (ADHD) autism spectrum disorder, and anorexia nervosa. The main outcome of interest was the diagnosis of CUD.

Results

The study included 88 637 individuals. PRS for schizophrenia did not predict CUD in controls [hazard ratio (HR) = 1.16, 95% CI 0.95–1.43 per standard-deviation increase in PRS, or HR = 1.47, 95% CI 0.72–3.00 comparing highest v. remaining decile], but PRS for ADHD did (HR = 1.27, 95% CI 1.08–1.50 per standard-deviation increase, or HR = 2.02, 95% CI 1.27–3.22 for the highest decile of PRS). Among cases with schizophrenia, the PRS for schizophrenia was associated with CUD. While CUD was a strong predictor of schizophrenia (HR = 4.91, 95% CI 4.36–5.53), the inclusion of various PRS did not appreciably alter this association.

Conclusion

The PRS for schizophrenia was not associated with CUD in controls or patients with other psychiatric disorders than schizophrenia. This speaks against the hypothesis that shared genetic vulnerability would explain the association between cannabis and schizophrenia.

Copyright

Corresponding author

Author for correspondence: Carsten Hjorthøj, E-mail: Carsten.hjorthoej@regionh.dk

References

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Carey, C. E., Agrawal, A., Bucholz, K. K., Hartz, S. M., Lynskey, M. T., Nelson, E. C., … Bogdan, R. (2016). Associations between polygenic risk for psychiatric disorders and substance involvement. Frontiers in Genetics, 7, 149.
Centonze, D., Bari, M., Di Michele, B., Rossi, S., Gasperi, V., Pasini, A., … Maccarrone, M. (2009). Altered anandamide degradation in attention-deficit/hyperactivity disorder. Neurology, 72, 15261527.
Cerdá, M., Wall, M., Feng, T., Keyes, K. M., Sarvet, A., Schulenberg, J., … Hasin, D. S. (2017). Association of state recreational marijuana laws with adolescent marijuana use. JAMA Pediatrics, 171, 142149.
Compton, W. M., Grant, B. F., Colliver, J. D., Glantz, M. D., & Stinson, F. S. (2004). Prevalence of marijuana use disorders in the United States: 1991–1992 and 2001–2002. JAMA, 291, 21142121.
Crespi, B., Stead, P., & Elliot, M. (2010). Comparative genomics of autism and schizophrenia. Proceedings of the National Academy of Sciences, 107, 17361741.
Demontis, D., Rajagopal, V. M., Thorgeirsson, T. E., Als, T. D., Grove, J., Leppälä, K., … Børglum, A. D. (2019). Genome-wide association study implicates CHRNA2 in cannabis use disorder. Nature Neuroscience, 22, 10661074.
Ferdinand, R. F., Sondeijker, F., van der Ende, J., Selten, J.-P., Huizink, A., & Verhulst, F. C. (2005). Cannabis use predicts future psychotic symptoms, and vice versa. Addiction (Abingdon, England), 100, 612618.
Fergusson, D. M., & Boden, J. M. (2008). Cannabis use and adult ADHD symptoms. Drug and Alcohol Dependence, 95, 9096.
Gandal, M. J., Haney, J. R., Parikshak, N. N., Leppa, V., Ramaswami, G., Hartl, C., … Geschwind, D. H. (2018). Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science, 359, 693697.
Grove, J., Ripke, S., Als, T. D., Mattheisen, M., Walters, R. K., Won, H., … Børglum, A. D. (2019). Identification of common genetic risk variants for autism spectrum disorder. Nature Genetics, 51, 431444.
Hiemstra, M., Nelemans, S. A., Branje, S., van Eijk, K. R., Hottenga, J.-J., Vinkers, C. H., … Boks, M. P. (2018). Genetic vulnerability to schizophrenia is associated with cannabis use patterns during adolescence. Drug and Alcohol Dependence, 190, 143150.
Hjorthøj, C., Uddin, M. J., Hougaard, D. M., Sørensen, H. J., & Nordentoft, M. (2019). Polygenic risk for psychiatric disorder and singleness in patients with severe mental illness and controls. Journal of Psychiatric Research, 119, 6066.
Kühl, J. O. G., Laursen, T. M., Thorup, A., & Nordentoft, M. (2016). The incidence of schizophrenia and schizophrenia spectrum disorders in Denmark in the period 2000–2012. A register-based study. Schizophrenia Research, 176, 533539.
Lee, S. H., Ripke, S., Neale, B. M., Faraone, S. V., Purcell, S. M., Perlis, R. H., … Wray, N. R. (2013). Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nature Genetics, 45, 984994.
Lynge, E., Sandegaard, J. L., & Rebolj, M. (2011). The Danish National Patient Register. Scandinavian Journal of Public Health, 39, 3033.
Macleod, J., Oakes, R., Copello, A., Crome, I., Egger, M., Hickman, M., … Davey Smith, G. (2004). Psychological and social sequelae of cannabis and other illicit drug use by young people: a systematic review of longitudinal, general population studies. Lancet, 363, 15791588.
Marconi, A., Di Forti, M., Lewis, C. M., Murray, R. M., & Vassos, E. (2016). Meta-analysis of the association between the level of Cannabis use and risk of psychosis. Schizophrenia Bulletin, 42, 12621269.
Mehmedic, Z., Chandra, S., Slade, D., Denham, H., Foster, S., Patel, A. S., … ElSohly, M. A. (2010). Potency trends of Δ9-THC and other cannabinoids in confiscated cannabis preparations from 1993 to 2008. Journal of Forensic Sciences, 55, 12091217.
Meier, S. M., Agerbo, E., Maier, R., Pedersen, C. B., Lang, M., Grove, J., … Mattheisen, M. (2016). High loading of polygenic risk in cases with chronic schizophrenia. Molecular Psychiatry, 21, 969974.
Moore, T. H. M., Zammit, S., Lingford-Hughes, A., Barnes, T. R. E., Jones, P. B., Burke, M., & Lewis, G. (2007). Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet, 370, 319328.
Mors, O., Perto, G. P., & Mortensen, P. B. (2011). The Danish Psychiatric Central Research Register. Scandinavian Journal of Public Health, 39, 5457.
Nielsen, S. M., Toftdahl, N. G., Nordentoft, M., & Hjorthøj, C. (2017). Association between alcohol, cannabis, and other illicit substance abuse and risk of developing schizophrenia: a nationwide population based register study. Psychological Medicine, 47, 16681677.
Ottosen, C., Petersen, L., Larsen, J. T., & Dalsgaard, S. (2016). Gender differences in associations between attention-deficit/hyperactivity disorder and substance use disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 55, 227234.
Pasman, J. A., Verweij, K. J. H., Gerring, Z., Stringer, S., Sanchez-Roige, S., Treur, J. L., … Vink, J. M. (2018). GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability. Nature Neuroscience, 21, 11611170.
Pasman, J. A., Verweij, K. J. H., & Vink, J. M. (2019). Systematic review of polygenic gene–environment interaction in Tobacco, Alcohol, and Cannabis Use. Behavior Genetics, 49, 349365.
Pedersen, C. B., Bybjerg-Grauholm, J., Pedersen, M. G., Grove, J., Agerbo, E., Bækvad-Hansen, M., … Mortensen, P. B. (2018). The iPSYCH2012 case-cohort sample: new directions for unravelling genetic and environmental architectures of severe mental disorders. Molecular Psychiatry, 23, 614.
Power, R. A., Verweij, K. J. H., Zuhair, M., Grant, W., Henders, A. K., Heath, A. C., … Martin, N. G. (2014). Genetic predisposition to schizophrenia associated with increased use of cannabis. Molecular Psychiatry, 19, 12011204.
Ripke, S., Neale, B. M., Corvin, A., Walters, J. T. R. R., Farh, K.-H. H., Holmans, P. A., … O’Donovan, M. C. (2014). Biological insights from 108 schizophrenia-associated genetic loci. Nature, 511, 421427.
Shi, Y., Lenzi, M., & An, R. (2015). Cannabis liberalization and adolescent Cannabis use: a cross-national study in 38 countries. PLoS ONE, 10, e0143562.
Toftdahl, N. G., Nordentoft, M., & Hjorthøj, C. (2016). Prevalence of substance use disorders in psychiatric patients: a nationwide Danish population-based study. Social Psychiatry and Psychiatric Epidemiology, 51, 129140.
Verweij, K. J. H., Abdellaoui, A., Nivard, M. G., Sainz Cort, A., Ligthart, L., Draisma, H. H. M., … Vink, J. M. (2017). Short communication: genetic association between schizophrenia and cannabis use. Drug and Alcohol Dependence, 171, 117121.
Volkow, N. D., Hampson, A. J., & Baler, R. D. (2017). Don't worry, be happy: endocannabinoids and Cannabis at the intersection of stress and reward. Annual Review of Pharmacology and Toxicology, 57, 285308.
Watson, H. J., Yilmaz, Z., Thornton, L. M., Hübel, C., Coleman, J. R. I., Gaspar, H. A., … Bulik, C. M., (2019). Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa. Nature Genetics, 51, 12071214.
Zulauf, C. A., Sprich, S. E., Safren, S. A., & Wilens, T. E. (2014). The complicated relationship between attention deficit/hyperactivity disorder and substance use disorders. Current Psychiatry Reports, 16, 436.

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No evidence of associations between genetic liability for schizophrenia and development of cannabis use disorder

  • Carsten Hjorthøj (a1) (a2) (a3), Md Jamal Uddin (a1) (a2), Theresa Wimberley (a2) (a4) (a5), Søren Dalsgaard (a2) (a4), David M. Hougaard (a2) (a6), Anders Børglum (a2) (a7), Thomas Werge (a2) (a8) and Merete Nordentoft (a1) (a2)...

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