Skip to main content Accessibility help
×
Home

Examining pathways between genetic liability for schizophrenia and patterns of tobacco and cannabis use in adolescence

  • Hannah J. Jones (a1) (a2) (a3), Gemma Hammerton (a1) (a2), Tayla McCloud (a4), Lindsey A. Hines (a1), Caroline Wright (a5), Suzanne H. Gage (a6), Peter Holmans (a7), Peter B Jones (a8), George Davey Smith (a2), David E. J. Linden (a7), Michael C. O'Donovan (a7), Michael J. Owen (a7), James T. Walters (a7), Marcus R. Munafò (a2) (a9), Jon Heron (a1) (a2) and Stanley Zammit (a1) (a7)...

Abstract

Background

It is not clear to what extent associations between schizophrenia, cannabis use and cigarette use are due to a shared genetic etiology. We, therefore, examined whether schizophrenia genetic risk associates with longitudinal patterns of cigarette and cannabis use in adolescence and mediating pathways for any association to inform potential reduction strategies.

Methods

Associations between schizophrenia polygenic scores and longitudinal latent classes of cigarette and cannabis use from ages 14 to 19 years were investigated in up to 3925 individuals in the Avon Longitudinal Study of Parents and Children. Mediation models were estimated to assess the potential mediating effects of a range of cognitive, emotional, and behavioral phenotypes.

Results

The schizophrenia polygenic score, based on single nucleotide polymorphisms meeting a training-set p threshold of 0.05, was associated with late-onset cannabis use (OR = 1.23; 95% CI = 1.08,1.41), but not with cigarette or early-onset cannabis use classes. This association was not mediated through lower IQ, victimization, emotional difficulties, antisocial behavior, impulsivity, or poorer social relationships during childhood. Sensitivity analyses adjusting for genetic liability to cannabis or cigarette use, using polygenic scores excluding the CHRNA5-A3-B4 gene cluster, or basing scores on a 0.5 training-set p threshold, provided results consistent with our main analyses.

Conclusions

Our study provides evidence that genetic risk for schizophrenia is associated with patterns of cannabis use during adolescence. Investigation of pathways other than the cognitive, emotional, and behavioral phenotypes examined here is required to identify modifiable targets to reduce the public health burden of cannabis use in the population.

Copyright

Corresponding author

Author for correspondence: Hannah J. Jones, E-mail: hannah.jones@bristol.ac.uk

References

Hide All
Amos, A., Wiltshire, S., Bostock, Y., Haw, S., & McNeill, A. (2004). 'You can't go without a fag … you need it for your hash' - a qualitative exploration of smoking, cannabis and young people. Addiction, 99(1), 7781. doi:10.1111/j.1360-0443.2004.00531.x.
Baron-Cohen, S., & Wheelwright, S. (2003). The friendship questionnaire: An investigation of adults with Asperger syndrome or high-functioning autism, and normal sex differences. Journal of Autism and Developmental Disorders, 33(5), 509517. doi:10.1023/a:1025879411971.
Boyd, A., Golding, J., Macleod, J., Lawlor, D. A., Fraser, A., Henderson, J., … Davey Smith, G. (2013). Cohort profile: The ‘children of the 90s’ - the index offspring of the Avon Longitudinal Study of Parents and Children. International Journal of Epidemiology, 42, 111127. doi:10.1093/ije/dys064.
Cannon, M., Walsh, E., Hollis, C., Kargin, M., Taylor, E., Murray, R. M., & Jones, P. B. (2001). Predictors of later schizophrenia and affective psychosis among attendees at a child psychiatry department. British Journal of Psychiatry, 178, 420426. doi:10.1192/bjp.178.5.420.
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. doi:10.3389/fgene.2016.00149.
Chang, C. C., Chow, C. C., Tellier, L. C. A. M., Vattikuti, S., Purcell, S. M., & Lee, J. J. (2015). Second-generation PLINK: Rising to the challenge of larger and richer datasets. Gigascience, 4, 7. doi:10.1186/s13742-015-0047-8.
Courtney, K. E., Mejia, M. H., & Jacobus, J. (2017). Longitudinal studies on the etiology of cannabis use disorder: A review. Current addiction reports, 4(2), 4352. doi:10.1007/s40429-017-0133-3.
Davey Smith, G., & Hemani, G. (2014). Mendelian randomization: Genetic anchors for causal inference in epidemiological studies. Human Molecular Genetics, 23(R1), R89R98. doi:10.1093/hmg/ddu328.
de Leon, J., & Diaz, F. J. (2005). A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors. Schizophrenia Research, 76(2–3), 135157. doi:10.1016/j.schres.2005.02.010.
Dickerson, F., Stallings, C. R., Origoni, A. E., Vaughan, C., Khushalani, S., Schroeder, J., & Yolken, R. H. (2013). Cigarette smoking among persons with schizophrenia or bipolar disorder in routine clinical settings, 1999–2011. Psychiatric Services, 64(1), 4450. doi:10.1176/appi.ps.001432012.
D'Souza, D. C., Perry, E., MacDougall, L., Ammerman, Y., Cooper, T., Wu, Y. T., … Krystal, J. H. (2004). The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: Implications for psychosis. Neuropsychopharmacology, 29(8), 15581572. doi:10.1038/sj.npp.1300496.
Fraser, A., Macdonald-Wallis, C., Tilling, K., Boyd, A., Golding, J., Davey Smith, G., … Lawlor, D. A. (2013). Cohort profile: The avon longitudinal study of parents and children: ALSPAC mothers cohort. International Journal of Epidemiology, 42, 97110. doi:10.1093/ije/dys066.
Gage, S. H., Davey Smith, G., Ware, J. J., Flint, J., & Munafò, M. R. (2016). G = E: What GWAS can tell us about the environment. Plos Genetics, 12, 2. doi:10.1371/journal.pgen.1005765.
Gage, S. H., Hickman, M., Heron, J., Munafo, M. R., Lewis, G., Macleod, J., & Zammit, S. (2014). Associations of cannabis and cigarette use with psychotic experiences at age 18: Findings from the Avon Longitudinal Study of Parents and Children. Psychological Medicine, 44(16), 34353444. doi:10.1017/S0033291714000531.
Gage, S. H., Hickman, M., & Zammit, S. (2016). Association between cannabis and psychosis: Epidemiologic evidence. Biological Psychiatry, 79(7), 549556. doi:10.1016/j.biopsych.2015.08.001.
Gage, S. H., Jones, H. J., Burgess, S., Bowden, J., Davey Smith, G., Zammit, S., … Munafò, M. R. (2017). Assessing causality in associations between cannabis use and schizophrenia risk: A two-sample Mendelian randomization study. Psychological Medicine, 47(5), 971980. doi:10.1017/S0033291716003172.
Goodman, R. (1999). The extended version of the strengths and difficulties questionnaire as a guide to child psychiatric caseness and consequent burden. Journal of Child Psychology and Psychiatry, and Allied Disciplines, 40(5), 791799. doi:10.1017/S0021963099004096.
Green, B., Young, R., & Kavanagh, D. (2005). Cannabis use and misuse prevalence among people with psychosis. British Journal of Psychiatry, 187, 306313. doi:10.1192/bjp.187.4.306.
Guloksuz, S., Pries, L. K., Delespaul, P., Kenis, G., Luykx, J. J., Lin, B. C. D., … van Os, J. (2019). Examining the independent and joint effects of molecular genetic liability and environmental exposures in schizophrenia: Results from the EUGEI study. World Psychiatry, 18(2), 173182. doi:10.1002/wps.20629.
Gurillo, P., Jauhar, S., Murray, R. M., & MacCabe, J. H. (2015). Does tobacco use cause psychosis? Systematic review and meta-analysis. The Lancet. Psychiatry, 2(8), 718725. doi:10.1016/S2215-0366(15)00152-2.
Handley, S. J., Capon, A., Beveridge, M., Dennis, I., & Evans, J. S. T. (2004). Working memory, inhibitory control and the development of children's reasoning. Thinking & Reasoning, 10(2), 175195. doi:10.1080/13546780442000051.
Heron, J. E., Croudace, T. J., Barker, E. D., & Tilling, K. (2015). A comparison of approaches for assessing covariate effects in latent class analysis. 6(4), 15. doi:10.14301/llcs.v6i4.322.
Horwood, J., Salvi, G., Thomas, K., Duffy, L., Gunnell, D., Hollis, C., … Harrison, G. (2008). IQ And non-clinical psychotic symptoms in 12-year-olds: Results from the ALSPAC birth cohort. British Journal of Psychiatry, 193, 185191. doi:10.1192/bjp.bp.108.051904.
Howe, L. J., Trela-Larsen, L., Taylor, M., Heron, J., Munafò, M. R., & Taylor, A. E. (2017). Body mass index, body dissatisfaction and adolescent smoking initiation. Drug and Alcohol Dependence, 178, 143149. doi:10.1016/j.drugalcdep.2017.04.008.
Hubbard, L., Tansey, K. E., Rai, D., Jones, P., Ripke, S., Chambert, K. D., … Zammit, S. (2016). Evidence of common genetic overlap between schizophrenia and cognition. Schizophrenia Bulletin, 42(3), 832842. doi:10.1093/schbul/sbv168.
Jones, H. J., Gage, S. H., Heron, J., Hickman, M., Lewis, G., Munafo, M. R., & Zammit, S. (2018). Association of combined patterns of tobacco and cannabis use in adolescence with psychotic experiences. JAMA Psychiatry, 75(3), 240246. doi:10.1001/jamapsychiatry.2017.4271.
Jones, H. J., Stergiakouli, E., Tansey, K. E., Hubbard, L., Heron, J., Cannon, M., … Zammit, S. (2016). Phenotypic manifestation of genetic risk for schizophrenia during adolescence in the general population. JAMA Psychiatry, 73(3), 221228. doi:10.1001/jamapsychiatry.2015.3058.
Koob, G. F., & Volkow, N. D. (2016). Neurobiology of addiction: A neurocircuitry analysis. The Lancet. Psychiatry, 3(8), 760773. doi:10.1016/S2215-0366(16)00104-8.
Liu, M. Z., Jiang, Y., Wedow, R., Li, Y., Brazel, D. M., Chen, F., … Vrieze, S. (2019). Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nature Genetics, 51(2), 237244. doi:10.1038/s41588-018-0307-5.
Malmberg, A., Lewis, G., David, A., & Allebeck, P. (1998). Premorbid adjustment and personality in people with schizophrenia. British Journal of Psychiatry, 172, 308313. doi:10.1192/bjp.172.4.308.
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 (London, England), 370(9584), 319328. doi:10.1016/S0140-6736(07)61162-3.
Muthén, L. K., & Muthén, B. O. (1998–2017). MPlus user's guide (8th ed.). Los Angeles, CA: Muthén & Muthén.
Pardiñas, A. F., Holmans, P., Pocklington, A. J., Escott-Price, V., Ripke, S., Carrera, N., … Walters, J. T. R. (2018). Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nature Genetics, 50(3), 381389. doi:10.1038/s41588-018-0059-2.
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 influence of schizophrenia. Nature Neuroscience, 21(9), 11611170. doi:10.1038/s41593-018-0206-1.
Power, R. A., Verweij, K. J. H., Zuhair, M., Montgomery, G. W., Henders, A. K., Heath, A. C., … Martin, N. G. (2014). Genetic predisposition to schizophrenia associated with increased use of cannabis. Molecular Psychiatry, 19(11), 12011204. doi:10.1038/mp.2014.51.
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A., Bender, D., … Sham, P. C. (2007). PLINK: A tool set for whole-genome association and population-based linkage analyses. American Journal of Human Genetics, 81, 559575. doi:10.1086/519795.
Purcell, S., Wray, N. R., Stone, J. L., Visscher, P. M., O'Donovan, M. C., & Sullivan, P. F., … International Schizophrenia Consortium (2009). Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature, 460, 748752. doi:10.1038/nature08185.
Reginsson, G. W., Ingason, A., Euesden, J., Bjornsdottir, G., Olafsson, S., Sigurdsson, E., … Stefansson, K. (2017). Polygenic risk scores for schizophrenia and bipolar disorder associate with addiction. Addiction Biology, 23(1), 485492. doi:10.1111/adb.12496.
Ripke, S., O'Dushlaine, C., Chambert, K., Moran, J. L., Kähler, A. K., Akterin, S., … Sullivan, P. F. (2013). Genome-wide association analysis identifies 14 new risk loci for schizophrenia. Nature Genetics, 45(10), 11501159. doi:10.1038/ng.2742.
Saccone, N. L., Wang, J. C., Breslau, N., Johnson, E. O., Hatsukami, D., Saccone, S. F., … Bierut, L. J. (2009). The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African-Americans and in European-Americans. Cancer Research, 69(17), 68486856. doi:10.1158/0008-5472.CAN-09-0786.
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014). Biological insights from 108 schizophrenia-associated genetic loci. Nature, 511, 421427. doi:10.1038/nature13595.
Stringer, S., Minica, C. C., Verweij, K. J. H., Mbarek, H., Bernard, M., Derringer, J., … Vink, J. M. (2016). Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32330 subjects from the International Cannabis Consortium. Translational Psychiatry, 6, e769. doi:10.1038/tp.2016.36.
Taylor, M., Collin, S. M., Munafò, M. R., MacLeod, J., Hickman, M., & Heron, J. (2017). Patterns of cannabis use during adolescence and their association with harmful substance use behaviour: Findings from a UK birth cohort. Journal of Epidemiology and Community Health, 71, 764770. doi:10.1136/jech-2016-208503.
Tobacco Genetics Consortium (2010). Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nature Genetics, 42(5), 441447. doi:10.1038/ng.571.
Valeri, L., & VanderWeele, T. J. (2013). Mediation analysis allowing for exposure-mediator interactions and causal interpretation: Theoretical assumptions and implementation with SAS and SPSS macros. Psychological Methods, 18(2), 137150. doi:10.1037/a0031034.
Varese, F., Smeets, F., Drukker, M., Lieverse, R., Lataster, T., Viechtbauer, W., … Bentall, R. P. (2012). Childhood adversities increase the risk of psychosis: A meta-analysis of patient-control, prospective- and cross-sectional cohort studies. Schizophrenia Bulletin, 38(4), 661671. doi:10.1093/schbul/sbs050.
Verweij, K. J. H., Abdellaoui, A., Nivard, M. G., Cort, A. S., 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. doi:10.1016/j.drugalcdep.2016.09.022.
Wechsler, D., Golombok, S., & Rust, J. (1992). Wechsler intelligence scale for children – third edition UK manual. Sidcup, UK: The Psychological Corporation.
Welham, J., Isohanni, M., Jones, P., & McGrath, J. (2009). The antecedents of schizophrenia: A review of birth cohort studies. Schizophrenia Bulletin, 35(3), 603623. doi:10.1093/schbul/sbn084.
Wolke, D., Woods, S., Bloomfield, L., & Karstadt, L. (2000). The association between direct and relational bullying and behaviour problems among primary school children. Journal of Child Psychology and Psychiatry, 41(8), 9891002. doi:10.1017/S0021963099006381.
Wootton, R. E., Richmond, R. C., Stuijfzand, B. G., Lawn, R. B., Sallis, H. M., Taylor, G. M. J., … Munafò, M. R. (2019). Evidence for causal effects of lifetime smoking on risk for depression and schizophrenia: a Mendelian randomisation study. Psychological Medicine, 19. doi:10.1017/S0033291719002678.

Keywords

Type Description Title
WORD
Supplementary materials

Jones et al. supplementary material
Jones et al. supplementary material

 Word (252 KB)
252 KB

Examining pathways between genetic liability for schizophrenia and patterns of tobacco and cannabis use in adolescence

  • Hannah J. Jones (a1) (a2) (a3), Gemma Hammerton (a1) (a2), Tayla McCloud (a4), Lindsey A. Hines (a1), Caroline Wright (a5), Suzanne H. Gage (a6), Peter Holmans (a7), Peter B Jones (a8), George Davey Smith (a2), David E. J. Linden (a7), Michael C. O'Donovan (a7), Michael J. Owen (a7), James T. Walters (a7), Marcus R. Munafò (a2) (a9), Jon Heron (a1) (a2) and Stanley Zammit (a1) (a7)...

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.